Radiation Oncology

HISTORY


Radiation Oncology  has been in use as a cancer treatment for more than 100 years, with its earliest roots traced from the discovery of x-rays in 1895 by ^{Wilhelm Roentgen} The field of radiation therapy began to grow in the early 1900s largely due to the groundbreaking work of Nobel Prize-winning scientist Marie Curie, who discovered the radioactive elements polonium and radium. This began a new era in medical treatment and research.Radium was used in various forms until the mid-1900s when cobalt and caesium units came into use. Medical linear accelerators have been used too as sources of radiation since the late 1940s.
With Godfrey Hounsfield’s invention of computed tomography (CT) in 1971, three-dimensional planning became a possibility and created a shift from 2-D to 3-D radiation delivery; CT-based planning allows physicians to more accurately determine the dose distribution using axial tomographic images of the patient's anatomy. Orthovoltage and cobalt units have largely been replaced by megavoltage linear accelerators, useful for their penetrating energies and lack of physical radiation source.
The advent of new imaging technologies, including magnetic resonance imaging (MRI) in the 1970s and positron emission tomography (PET) in the 1980s, has moved radiation therapy from 3-D conformal to intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) Tomotherapy. These advances allowed radiation oncologists to better see and target tumors, which have resulted in better treatment outcomes, more organ preservation and fewer side effects.
Thirty or forty years ago, the ability to diagnose and treat an individual with a brain tumor was limited by crude surgical and radiological tools. Modern neurosurgical tools and techniques and advanced imaging modalities such as CT and MRI now allow brain tumors to be identified much earlier in the course of the disease. Even when a cure is not possible, an earlier diagnosis can result in an improved outcome for the patient through more appropriate utilization of radiation therapy.
Radiation therapy uses high energy light beams (X-rays or gamma rays) or charged particles (electron beams or proton beams) to damage critical biological molecules in tumor cells. If enough damage is done to the chromosomes of a cell, it will spontaneously die or it will die the next time it tries to divide into two cells. Radiation therapy is usually done on an outpatient basis with treatment occurring each workday for a period of several weeks. If the patient has had surgery for the tumor, radiation therapy typically begins a week or two after surgery.
Radiation therapy is an effective cancer therapy. In surgery, a surgeon may be constrained in resecting the cancer by the presence of critical structures that cannot be removed. The side effects of chemotherapy on normal tissues far away from the brain may limit the ability of a medical oncologist to deliver appropriately intensive treatment to a brain tumor. In radiation therapy, a non-invasive treatment can be given repetitively over several weeks to months and can be aimed specifically at the area where treatment is needed, minimizing side effects for uninvolved normal tissues.
This repetitive treatment is called fractionation because a small fraction of the total dose is given in each treatment. The skills of the radiation oncologist, physicist and dosimetrist allow complex plans to be devised to minimize side effects for normal tissues. Radiotherapy can only be performed with linear accelerator technology.
Conventionally administered external beam radiation therapy gives a uniform dose of radiation to the entire region affected by the tumor. There is only a small variation of the dose delivered to various parts of the tumor. Radiation therapy may not be as effective as stereotactic radiosurgery, which can give higher doses of radiation to the tumor itself.
Treatment of brain tumors with external beam radiation therapy has been an area of intense research activity over the past several decades. Through clinical research, conducted on patients, much has been learned about how to appropriately use radiation therapy for various types of brain tumors. External beam radiation therapy is a valuable component of therapy for nearly all brain tumors; treatment can be delivered to any part, or all, of the central nervous system. The ability to assure uniform doses of radiation to the areas being treated is one of the major strengths of modern external beam radiation therapy.

THREE MAIN DIVISIONS OF RADIATION THERAPY

•     External Beam Therapy (EBRT or XRT)

External beam therapy (EBT) is a method for delivering a beam of high-energy x-rays to a patient's tumor. The beam is generated outside the patient (usually by a linear accelerator, see below) and is targeted at the tumor site. These high energy x-rays can deposit their dose to the area of the tumor to destroy the cancer cells and, with careful treatment planning, spare the surrounding normal tissues. No radioactive sources are placed inside the patient's body.

•   Brachytherapy  or  Unsealed Source Radiotherapy

Brachytherapy is an advanced cancer treatment. Radioactive seeds or sources are placed in or near the tumor itself, giving a high radiation dose to the tumor while reducing the radiation exposure in the surrounding healthy tissues. The term "brachy" is Greek for short distance. Brachytherapy is radiation therapy given at a short distance: localized, precise, and high-tech.

•    Particle Therapy

using beams of energetic protons, neutrons, or positive ions for cancer treatment. The most common type of particle therapy as of 2009 is proton therapy. Although a photon, used in x-ray or gamma ray therapy, can also be considered a particle, photon therapy is not considered here. Additionally, electron therapy is generally put into its own category. Because of this, particle therapy is sometimes referred to, more correctly, as hadron therapy (that is, therapy with particles that are made of quarks).






                      KEY ROOTS OF DISCOVERING RADIATION THERAPY

Radiation therapy has been in use as a cancer treatment for more than 100 years, with its earliest roots traced from the discovery of x-rays in 1895 by Wilhelm Röntgen.^[8]








The field of radiation therapy began to grow in the early 1900s largely due to the groundbreaking work of Nobel Prize-winning scientist Marie Curie, who discovered the radioactive elements polonium and radium. This began a new era in medical treatment and research.^[8] Radium was used in various forms until the mid-1900s when cobalt and caesium units came into use. Medical linear accelerators have been used too as sources of radiation since the late 1940s.

  With Godfrey Hounsfield’s invention of computed tomography (CT) in 1971, three-dimensional planning became a possibility and created a shift from 2-D to 3-D radiation delivery; CT-based planning allows physicians to more accurately determine the dose distribution using axial tomographic images of the patient's anatomy. Orthovoltage and cobalt units have largely been replaced by megavoltage linear accelerators, useful for their penetrating energies and lack of physical radiation source.





The advent of new imaging technologies, including magnetic resonance imaging (MRI) in the 1970s and positron emission tomography (PET) in the 1980s, has moved radiation therapy from 3-D conformal to intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) Tomotherapy. These advances allowed radiation oncologists to better see and target tumors, which have resulted in better treatment outcomes, more organ preservation and fewer side effects.




 TYPES



Intensity Modulated Radiation Therapy (IMRT)


Intensity-modulated radiation therapy (IMRT) is an advanced form of three-dimensional conformal radiotherapy (3DCRT). It uses sophisticated software and hardware to vary the shape and intensity of radiation delivered to different parts of the treatment area. It is one of the most precise forms of external beam radiation therapy available.
Like conventional 3DCRT, IMRT links CT scans to treatment planning software that allows the cancerous area to be visualized in three dimensions. However, regular 3DCRT and IMRT differ in how the pattern and volume of radiation delivered to the tumor is determined. In conventional 3DCRT, clinicians input delivery patterns into the computer. In IMRT, the physician designates specific doses of radiation (constraints) that the tumor and normal surrounding tissues should receive. The physics team then uses a sophisticated computer program to develop an individualized plan to meet the constraints. This process is termed "inverse treatment planning." Treatment with IMRT is slightly longer that with 3DCRT, but generally produces fewer side effects.
IMRT uses the same medical linear accelerators that deliver x-ray beams in conventional 3DCRT.
As a unique feature, it also involves dynamic multi-leaf collimators (DMLCs), computer-controlled devices that use up to 120 movable "leaves" to conform the radiation beam to the shape of the tumor from any angle, while protecting normal adjacent tissue as much as possible.
DMLCs allow the dose of radiation to vary within a single beam – in other words, to deliver higher radiation in some areas and lower radiation in others. Earlier technology could also shape radiation beams but could deliver them only at a single, constant dose. The ability to vary the radiation dose with DMLCs is accomplished by "sliding windows" of radiation beams across the target cancerous area.
To more easily picture how DMLCs work, imagine a shower head with many nozzles, with the water representing radiation. Standard radiation techniques only allow a constant flow of water to be delivered through all nozzles. But with DMLCs, individual nozzles may be turned off and on, or set to deliver water at different intensities. In radiation therapy, the net effect is that radiation doses can be "wrapped" around tumors, or "painted" within tumors, far more precisely than was previously possible.
Treatment process and side effects for IMRT are similar to those for 3DCRT.




Image-Guided Radiotherapy (IGRT)


Image-guided radiation therapy (IGRT) is the process of frequent two and three-dimensional imaging, during a course of radiation treatment, used to direct radiation therapy utilizing the imaging coordinates of the actual radiation treatment plan. The patient is localized in the treatment room in the same position as planned from the reference imaging dataset. An example of Three-dimensional (3D) IGRT would include localization of a cone-beam computed tomography (CBCT) dataset with the planning computed tomography (CT) dataset from planning. Similarly Two-dimensional (2D) IGRT would include matching planar kilovoltage (kV) radiographs fluoroscopy or megavoltage (MV) images with digital reconstructed radiographs (DRRs) from the planning CT.
This process is distinct from the use of imaging to delineate targets and organs in the planning process of radiation therapy. However, there is clearly a connection between the imaging processes as IGRT relies directly on the imaging modalities from planning as the reference coordinates for localizing the patient. The variety of image gathering hardware used in planning includes Computed Tomography(CT), Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET) among others. Through advancements in imaging technology, combined with a further understanding of human biology at the molecular level, the impact of IGRT on radiotherapy treatment continues to evolve.




Stereotactic Radiosurgery (SRS)


Stereotactic radiosurgery works the same as all other forms of radiation treatment. It does not remove the tumor or lesion, but it distorts the DNA of the tumor cells. The cells then lose their ability to reproduce and retain fluids. The tumor reduction occurs at the rate of normal growth for the specific tumor cell. In lesions such as AVMs (a tangle of blood vessels in the brain), radiosurgery causes the blood vessels to thicken and close off. The shrinking of a tumor or closing off of a vessel occurs over a period of time. For benign tumors and vessels, this will usually be 18 months to two years. For malignant or metastatic tumors, results may be seen in a few months, because these cells are very fast-growing.




Stereotactic Body Radiation Therapy (SBRT)

Stereotactic body radiation therapy (SBRT) is a technique designed to deliver radiation therapy very precisely to tumors anywhere in the body.  The word stereotactic pertains to the precise positioning of a tumor in relationship to the body.  The technology used in SBRT allows external beam radiation to be delivered with pinpoint accuracy.  With SBRT the physician can even take into account movement of a tumor based on a patient’s breathing pattern.  Such advancement in accuracy of radiation treatments allows higher doses of radiation to be delivered, thus potentially improving the likelihood of killing the cancer cells of a tumor.  Another benefit to improved accuracy is that treatments can be completed in a short period of time.  Typically, SBRT consists of 3 to 5 treatments carried out over the course of 1 to 2 weeks.  The precision associated with SBRT simultaneously helps reduce the dose of radiation to normal tissue around a tumor, thus helping to reduce side effects for patients.




3-Dimensional Conformal Radiotherapy

Three-dimensional conformal radiotherapy (3DCRT) is a complex process that begins with the creation of individualized, 3D digital data sets of patient tumors and normal adjacent anatomy. These data sets are then used to generate 3D computer images and to develop complex plans to deliver highly "conformed" (focused) radiation while sparing normal adjacent tissue. Because higher doses of radiation can be delivered to cancer cells while significantly reducing the amount of radiation received by surrounding healthy tissues, the technique should increase the rate of tumor control while decreasing side effects.

3DCRT is used to treat tumors that in the past might have been considered too close to vital organs and structures for radiation therapy. For example, 3DCRT allows radiation to be delivered to head and neck tumors in a way that minimizes exposure of the spinal cord, optic nerve, salivary glands and other important structures.



      
            SIDE EFFECTS

• Side effects of radiation therapy will depend on the type of radiation received, the amount of the surface of the brain targeted, the site targeted, and the total dose of radiation. In general, there will be hair loss, skin irritation, possible hearing problems, nausea, vomiting, loss of appetite, and neurologic effects. The most prevalent side effect is fatigue which is may last through treatment and for many months afterwards. The neurologic effects most affecting quality of life are eventual permanent memory and speech problems. These are just a few of the problems that can develop.

          Some specific indications for radiation therapy are discussed below.

Brain Metastases  

Cancers arising outside the brain in such diverse organs as the lung or breast can travel through the blood vessels to grow in the brain. Tumors that have spread in this fashion are known as metastases. Metastases may be discovered before or after they cause symptoms; a CT scan or an MRI are the tests most frequently used to diagnose brain metastases. Brain metastases may develop at different times (early or late) in the course of the disease in different patients.
Whole brain irradiation is frequently prescribed for patients with brain metastases. This treatment uses radiation to treat the visible lumps of tumor and the presumed invisible tumor deposits that are so small they may not be seen on even a sensitive MRI scan. Therefore, large areas of the brain may be treated to stop the spread of the tumors.
Symptoms caused by tumors metastatic to the brain usually respond to whole brain radiation therapy; different studies have reported response rates of 50 to 70 percent.
The Radiation Therapy Oncology Group (RTOG) performed randomized studies that showed a course of 10 treatments over two weeks to give a total dose of 30 Gray (the same as 3000 centiGray or 3000 rads, to use older terms) was as good as more extended courses of radiation therapy that give higher doses. In some situations, a shorter or longer course of treatment than two weeks may be preferable. For patients who have a single brain metastasis that is removed surgically, whole brain radiation therapy was found in a randomized study to give great improvements in preventing cancer from regrowing in the brain and in prolonging survival.
Stereotactic radiosurgery can be combined with whole brain radiation therapy for brain metastases. The whole brain radiation therapy will treat the visible metastases and any presumed microscopic tumor deposits as well. This is possible because whole brain radiation therapy is given as a low dose to a larger volume and targeted to the tumor and the area of possible tumor spread, while stereotactic radiosurgery is a high dose given to a very small volume and targeted only within the tumor itself. The two treatment techniques can be thought of as complementary in achieving control of metastases to the brain.
Whole brain radiation therapy can cause shrinkage of visible brain metastases, sometimes making them more amenable to stereotactic radiosurgery or microsurgery. The addition of whole brain radiation therapy to stereotactic radiosurgery can decrease the possibility of additional metastatic lesions and decrease the chance that visible lesions treated with radiosurgery may have recurrences after radiosurgical treatment. Omission of whole brain radiation therapy for brain metastases is slightly controversial, but this is an area of ongoing intensive research.
Recently, some investigators have tried stereotactic radiosurgery alone without whole brain radiation therapy for selected patients with brain metastases to avoid causing the side effects of whole brain radiotherapy. Because whole brain radiation therapy can be given at a later date to these patients if their metastases are not controlled by the radiosurgery, this strategy may relieve symptoms effectively while not adversely affecting survival.
There is a widely accepted belief that for melanoma, kidney cancer and sarcomas that spread to the brain, stereotactic radiosurgery may be more effective at controlling the lesions than whole brain radiation therapy. The Eastern Cooperative Oncology Group (ECOG) is evaluating radiosurgery as a solitary treatment for patients with one to three brain metastases of these types of tumors.

 

 

Meningiomas  

Meningiomas are tumors arising from the meninges, one of the protective layers surrounding the brain and its cushioning cerebrospinal fluid. They are usually slow-growing tumors that do not spread to other places in the brain or elsewhere in the body.
It is generally acknowledged that an operation that completely removes a meningioma does not require radiation therapy afterwards to prevent regrowth. An operation in an area where it is difficult for the surgeon to completely remove the meningioma from the surface of the brain can leave tumor cells behind that can lead to tumor regrowth.
For meningiomas that are completely removed, approximately 20 percent will regrow in 10 years and 33 percent by 15 years's time. Up to one third of patients with meningiomas who undergo an operation will be left with obvious residual tumor. More than half of patients with residual tumor after an operation will have regrowth of the tumor by 10 years's time and about 10 percent will not have had regrowth by 15 years's time.
Patients with meningiomas that are unresectable because of the extent or location of the tumor may be offered radiation therapy to try to prevent its further growth. There have been no randomized controlled (phase III) trials evaluating the effectiveness of a course of irradiation in preventing meningiomas from recurring after an operation, but radiation therapy is recognized as helpful in this role. Various researchers have found the control rates for incompletely resected meningiomas treated with radiation therapy as being in the range of 75 to 90 percent at 10 years. A significant decrease in post-radiation recurrences occurred when radiation oncologists started using MRI and CT scans to plan the radiation therapy. It was then possible to avoid accidentally missing the meningiomas when administering treatment! The University of California San Francisco has reported that the five-year recurrence rate for incompletely resected meningiomas after radiotherapy in the modern era is only 2 percent.

 

 

Pituitary Adenomas   

There has been less of a role for radiation therapy in the management of pituitary tumors in recent years because of progress in multidisciplinary medical management of the benign tumors arising in this important endocrine organ.
Improved neurosurgical technology and microsurgical techniques have also led to less of a need for postoperative radiation therapy to prevent regrowth of incompletely removed tumors. High resolution MRI imaging and sensitive hormone analyses can help assess the completeness of resection of tumors. Medications can help suppress hormone hypersecretion from some pituitary adenomas.
Many patients who have pituitary tumors that cannot be completely removed with surgery are offered stereotactive radiosurgery to try to prevent recurrence or further growth of the tumor. This is sometimes not possible because of proximity of the optic nerves to the pituitary tumor and because treating the tumor with an effective dose of irradiation may cause damage to the optic nerves, resulting in a loss of vision. A five- to six-week course of external beam radiation therapy has been shown to be effective in preventing further growth of these tumors with a low risk of damage to vision and has even been shown to improve vision when unresectable tumor is pressing on the optic nerves.
There have been no randomized controlled (phase III) trials evaluating the effectiveness of radiation therapy to prevent regrowth of pituitary tumors and there have been no similar trials to comparatively evaluate stereotactic radiosurgery and external beam radiation therapy. Stereotactic radiosurgery with its precise targeting may offer a good alternative after surgery for these types of tumors. As with meningiomas, it is most common to use either radiosurgery or radiation therapy for a pituitary adenoma, reserving the other treatment technique for any failures to control the pituitary tumor.
Radiation therapy for pituitary tumors has been associated with delayed side effects. The normal pituitary gland can produce decreased hormone levels following a course of radiation therapy, resulting in the need for hormone supplementation. It has been argued that this results from the radiation being given to the hypothalamic region of the brain (just above the pituitary). Follow-up of patients currently being treated with stereotactic fractionated radiotherapy may help determine whether this technological advance decreases these late side effects by more precise irradiation of the pituitary gland. Long-term follow-up has shown that patients treated with radiation therapy for residual pituitary tumors have a slightly increased risk of developing second tumors a decade or more after their irradiation. More precise, modern irradiation techniques may decrease the incidence of second tumors.

 

 

Gliomas and Malignant Tumors  

This group of tumors arises from the cells supporting the neurons in the brain. Some of these tumors initially present as low-grade, slowly -growing masses and can eventually progress to more aggressive, high-grade tumors. There are also tumors that are more aggressive and malignant at their outset.
This group includes astrocytoma and oligodendroglioma as well as tumors in which these cell types are combined oligoastrocytomas or mixed gliomas. More aggressive tumors have the word anaplastic in their descriptive name. The most aggressive type of glioma is called glioblastoma multiforme. Anaplastic gliomas and glioblastoma multiforme are termed malignant gliomas and represent approximately 40 percent of all brain tumors.
Malignant gliomas will spread from the site of origin to other areas in the brain but will almost never spread outside the brain. There is typically a gradient of infiltrating tumor cells that decreases as the distance from the margin increases. Most commonly, the tumor will recur at the same location that it started or immediately adjacent thereto. Radiation therapy treatment recommendations for malignant gliomas currently advise that several centimeters of apparently normal brain tissue around the tumor be treated to try to prevent these tumors from recurring at the edge of the area where the radiation is given.
A current study being run by the RTOG is using 3D conformal treatment and dose escalation to evaluate whether this promising technology can safely deliver higher doses of radiation to the tumor in patients who have had an operation for glioblastoma multiforme. Prior studies have not shown any benefit from higher doses of radiation than is conventionally given over six weeks's time, but it is hoped that modern technology may help limit the dose of radiation to normal brain tissue to a greater extent than was previously possible. If this can be safely done, one outcome may be improved survival from lower failure rates, but this remains to be proven.
Current trials are underway evaluating the role of chemotherapy in the treatment of malignant gliomas and low-grade gliomas. Oligodendrogliomas seem to be more responsive to chemotherapy than other gliomas. There have been promising initial results. New drugs active against gliomas will be found through these trials and physicians will learn how best to integrate them with surgery and radiation therapy.

• Radiation treatments affect all cells that are targeted. This means where normal healthy cells are targeted along with tumor cells, there will be injury to the healthy cells. The Merck Manual states the following:

          Radiation Injury to the Nervous System: The nervous system can be damaged by radiation therapy.      Acute and subacute transient symptoms may develop early, but progressive, permanent, often disabling nervous system damage may not appear for months to years. The total radiation dose, size of the fractions, duration of therapy, and volume of [healthy brain] nervous tissue irradiated influence the likelihood of injury. Considerable variation in individual susceptibility complicates the effort to predict safe radiation doses. (Source: The Merck Manual of Diagnosis and Therapy, Section 14, Neurologic Disorders.)

Side-effects of radiation are caused by the radiation treatment’s affect on normal cells with some being minimal and other being permanent. Additionally, the effects may occur quickly (acute) or months and years after treatment.

Acute reactions occur during or immediately after radiation. They are normally caused by swelling and can be easily controlled with medications. Delayed or late reactions are normally permanent and can be progressive. They can vary from mild to severe and may include decreased intellect, memory impairment, confusion, personality changes among other changes. All symptoms would be dependent on the amount of healthy tissue targeted with radiation.

Oncogenesis, the development of another tumor from the radiation treatment to the brain, is now a recognized, although rare, possible long-term side-effect of radiation to the brain. When another tumor occurs it is rare, and is most often associated with whole brain radiation or with fractionated radiotherapy. Each of these target more healthy brain tissue than one-session radiosurgery.