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INTRODUCTION

Stereotactic radiosurgery - Gamma Knife® is a type of external-beam radiation therapy that makes use of intricate technology to precisely locate and irradiate tumors or vascular malformations within the head and brain. Despite its name, Gamma Knife is a non-invasive surgery which does not actually involve any knife, scalpel, or incision; the “knife” in this case refers to multiple intensely focused beams of gamma radiation targeted at the area of concern, slowly shrinking it. The procedure can be used to treat targets even in the most critical, difficult-to-access areas of the brain without delivering significant radiation doses to healthy normal brain tissue. Gamma Knife is the tried-and-true treatment for virtually any intracranial pathology, with more than 800,000 patients treated worldwide thus far (Elekta, 2017). That’s not all, the constantly evolving technology also gave rise to Stereotactic body radiation therapy, which modifies the original concept to permit treatment of small tumors that lie outside the brain and spinal cord.

BRIEF HISTORY

Originally termed by Swedish professor Lars Leksell (1907-1986), stereotactic radiosurgery (SRS) is a technique for the non-invasive destruction of intracranial tissues or lesions that may be inaccessible or unsuitable for open surgery (Leksell, 1983). “Stereotactic radiosurgery” can be loosely translated as guided surgery using radiation. The first stereotactic instrument was designed in the 1950s for use with probes and electrodes. The principle of the instrument was to place the affected target in the center of a semicircular arc, which made it easily adaptable for cross-firing the target with concentrated beams of proton radiation from an x-ray tube. Although this concept was effective in destroying deep brain structure with no risk of bleeding or infection, it proved too complex and costly.

EVOLUTION OF THE GAMMA KNIFE SYSTEM

In 1967, Leksell selected Cobalt-60 as the photon radiation source and development of the first Gamma Knife unit began. Cobalt-60 is a radioactive form of cobalt, prepared by exposing cobalt to the radiations of an atomic pile. It is widely used in medical science in place of X-rays or radium in the inspection of materials to reveal internal structure, flaws, or foreign objects. Cobalt-60 is preferred over radium (another radioactive element) due to its lower cost, high durability, more homogenous gamma radiation, and softer beta radiation, which can be easily filtered out in the absence of contamination, along with its ability to be machined or shaped in any form before irradiation to fit special requirements (Roland, 2013). The prototype Gamma Knife created a discoid-shaped lesion suitable for neurosurgical treatment of movement disorder surgery, and intractable pain management (Niranjan, 2010). Upon the success of the first unit and realization of the potential of stereotactic radiosurgery for treating brain tumors, Professor Leksell developed a second, re-engineered Gamma Knife in 1975. It was installed in Karolinska Institute, and the new spheroidal lesion was utilized for the treatment of intracranial tumors and vascular malformations. The third and fourth units were installed in Buenos Aires, Argentina, and Sheffield, England in the 1980s (Niranjan, 2010).

In 1999, Gamma Knife was finally introduced to North America with the installation of the fifth unit, termed model C at the University of Pittsburgh Medical Center. This technology combines dose planning advances with robotic engineering. The unit incorporated an automatic positioning system with submillimetric accuracy, used to move the frame to each coordinate. This system removes the need to manually adjust each set of coordinates and also the time spent removing the patient from the helmet to set the new coordinates, significantly reducing the time spent to complete the procedure and also increased accuracy and safety (Niranjan, 2010). The device was initially approached with caution. However, gradual radiosurgery successes for benign tumors and vascular malformations led to a great rise of radiosurgery cases and sales of radiosurgical units. In recent years, metastatic brain tumors have become the most common indication of radiosurgery. Brain metastases now comprise 30-50% of radiosurgery cases at busy centers (Niranjan, 2010).

The slow development of radiosurgery has been due to the absolutely need for a precise localization of the target. The introduction of three-dimensional imaging modalities, such as Computed Tomography and Magnetic Resonance Imaging produced a revolution in stereotactic localization. These exams are now used in tandem with SRS to locate abnormalities within the body and define their exact sizes and shapes; the images also act as guides for the treatment planning, allowing careful positioning of the patient for therapy sessions. The limitation of the Gamma Knife is mainly its usability outside the head, although the new generation of Gamma Knife can treat tumors up to C2 vertebra level (Kurup, 2010).

As of today, Leksell Gamma Knife Icon is the most advanced, precise iteration of the Gamma Knife models. It offers a reported accuracy of 0.15mm, which is six times better than industry standard. The integrated real-time motion management ensures radiation will be blocked once patient moves outside of pre-set theshold. This newer model allows frameless immobilization without compromising precision (Elekta, 2017).

TECHNICAL FACTORS

Inside the gamma unit lies an array of Cobalt-60 sources which are aligned with a collimation system. The collimation system concentrates individual beams of gamma radiation very precisely to a focus point. Individually, these beams have relatively low dose rate and cause minimal biological effect. However, the superposition of all beam at a focus point have a much higher dose rate. Due to this mechanic, the Gamma Knife can concentrate on target areas of tissue without causing significant collateral damage to areas outside the targeted area. (UVA, 2017)

Patients are selected for treatment after thorough investigation of previous records and imaging studies. A stereotactic head frame is affixed to the patient’s head before the Gamma Knife procedure. This frame provides a reference coordinate system that allows points in the brain to be precisely located. During the frame placement, the patient will receive a mild sedative administered in the OR by an anesthesiologist in order to provide a pain-free placement. Then, advanced imaging technology such as computed tomography (CT), angiography, or magnetic resonance imaging (MRI) is performed to determine patient’s condition and the location of tumor, with MRI being the preferred modality and CT as an alternative. Finally, the patient’s head is placed within a large device resembling a helmet with small openings called “collimator ports.” Radiation beams are then adjusted through these ports to direct the appropriate amount of energy precisely at the target tissue. Patient may experience minimal discomfort during the procedure and will be able to communicate with the physician through a microphone installed in the helmet as necessary (UVA, 2017). The treatment team typically consists of a radiation therapist, a nurse, radiologist, oncologist, and physicist.

With newer Gamma Knife models, particularly the commonly used Leksell Gamam Knife PERFEXION, radiation administration during the procedure is performed from the control computer and is a fully automated process including set up of the stereotactic coordinates, set up of various sector positions defining collimator size or blocked beams and set up of exposure times. All treatment data are exported to the operating console. The only manual portion of the procedure is the positioning of the patient’s head and the adjustment of the couch height to ensure optimal comfort for the patient (Niranjan, 2010).

INTRODUCTION OF CYBERKNIFE

A ‘linear accelerator’-based radiosurgery was pioneered in the mid-1980s. These systems differ from the original Gamma Knife system mainly due to the fact they use 6-MV x-rays produced from linear accelerator, instead of gamma rays from Co-60 sources. They also use mini-multileaf collimator by way of treating irregular lesions in the brain. Just like Gamma Knife, a stereotactic frame is required to be fixed onto the patient’s head (Kurup, 2010). Although the designs of 2 systems were different, the core concept were the same and there was no clear proof on which was more clinically efficient than the other. That is, until Cyberknife came into play.

Following the success of Gamma Knife, stereotactic body radiation therapy (SBRT) was researched and developed. SBRT, as the name implies, is designed to treat tumors that lie outside the brain and spinal cord. Since these tumors have the tendency to move along with the normal motion of the body, they cannot be targeted as accurately as tumors within the brain or spine. Due to this, SBRT is usually given in more than one dose. SBRT systems are typically referred to by their brand names, the most well-known is Cyberknife® (NCI, 2010). The Cyberknife concept was originally adopted by professor John Adler, a neurosurgeon at Stanford University Medical Center. After completing a fellowship in Sweden with Lars Leksell, Adler developed the first Cyberknife system in 1987. Adler’s vision was to create a non-invasive robotic radiosurgery system that can treat tumors anywhere in the body with great accuracy. This concept reached far beyond the practice of radiosurgery at the time, so the system was initially put to use for treatment of only intracranial lesions (Kurup, 2010).

What makes Cyberknife different from other stereotactic radiosurgery systems is the use of an industrial robotic arm, paired with a lightweight linear accelerator. This flexible arm has 6 degrees of freedom of movement, unlike the conventional linear accelerator, which has only rotational movement in one plane. CyberKnife treatments are non-isocentric, where beams can be directed from any desired angle (Kurup, 2010). This system does not require a frame to be attached onto the patient’s skull for setup and verification. Cyberknife has sub-millimeter accuracy in tracking tumor position. The system is programmed to issue warning and stop treatment if sub-millimeter accuracy is not achieved. There are 5 different tumor-tracking facilities in Cyberknife treatment. They are 6D skull, fiducial, X sight spine, X sight lung with synchrony, and fiducial with synchrony. These tracking methods are used in different types of sites and with various natures of the organ to be treated. 6D skull tracking is only used for intracranial lesions. Fiducial tracking is used for any other site. The synchrony tracking is used for tracking any moving target in a phased manner with breathing cycles. Unlike other systems, where treatment is given during certain fixed phase of breathing, with synchrony method, the robot can move in synch with chest movement during breathing and deliver radiation with no interruption as if the tumor is locked to the beam (Kurup, 2010).

Now, thanks to advanced technologies and years of research, the Cyberknife has attained maximum flexibility in its use to treat any lesion in any part of the body noninvasively. However, the system also has limitations, particularly the prolonged treatment time, ranging from 30 to 60 minutes. Large volumes are not suitable with Cyberknife as the principle of delivery is ‘dose painting’ from one edge of the tumor to the other. This is most suitable for recurrent and residual tumors after prior radiotherapy treatments (Kurup, 2010). The concept of ‘dose painting’ was a concept adopted in radiation therapy. It is the description of a non-uniform radiation dose distribution to the target volume based on functional or molecular images shown to be indicative of the local risk of relapse (Bentzen & Gregoire, 2011). Other than brain lesions, small tumors in lung, liver, and spine can be effectively treated using Cyberknife (Kurup, 2010).

Just like Gamma Knife, a high degree of understanding and training essential and is emphasized before the system is put to use in clinical practice by any center. The team consists of radiation oncologists, medical physicists, and technologists. Clinicians should understand the tumor biology of short-course treatment with high dose/fraction. The radiation therapy technologist should know the principles, the accuracy desired and achievable and consequences of errors corrected and their impact on treatment delivery (Kurup, 2010).

COMMON PATHOLOGY

The treatment of SRS includes but is not limited to meningiomas, acoustic neuromas, metastases, and arteriovenous malformations. Theoretically, SRS is able to treat any cranial tumor/lesions that conventional surgery can, without the associated risks. One of the most prominent pathology which SRS is an ideal treatment of is brain metastases. The term metastasis, metastatic brain tumor, or secondary brain tumor refer to cancer that begins elsewhere in the body and spreads to the brain. Brain metastasis can present as a single tumor or multiple tumors (ABTA, 2016).

Metastatic brain tumors affect approximately 200,000 - 300,000 people per year. With 10-20% metastatic brain tumors arise as a single tumor and 80+% as multiple tumors within the brain. The incidence begins to increase in individuals 45-64 years of age and is highest in people over 65 (ABTA, 2016). Metastatic brain tumors begin when cancerous cells in another organ of the body spread to the brain via circulatory system. Since blood from the lungs flows directly to the brain, lung cancer is capable of quickly spreading to the brain. Sometimes, this can happen to fast that the brain metastases are detected before the primary lung cancer is found. Due to this, lung cancer are the most common type of brain metastases in both men and women. Other types include breast cancer, melanoma metastases, colon/colorectal metastases, and kidney/renal metastases (ABTA, 2016).

Symptoms are related to the location of the tumor within the brain. Each brain controls specific body functions. Symptoms surface when areas of the brain no longer function properly. Headache and seizures are the two most commons symptoms. Cognitive disturbances is another common symptom of a metastatic brain tumor. These may include difficulty with memory, or shifts in personality and behavior. Motor problems may occur, such as weakness on one side of the body or an unbalanced walk, relative to the responsible part in the brain where the tumor resides. Tumors in the spine may cause back pain, weakness or changes in sensation in an extremity, or loss of bladder/bowel control (ABTA, 2016).

Gamma Knife radiosurgery (GKRS) is generally recommended for small tumors (3 cm or less). It can be used to treat tumors that are not easily accessible with conventional surgery, such as those located deep within the brain. GKRS may also be used to recurrences if whole-brain radiation was previously given, or as a local “boost” following a whole-brain radiation. In more recent years, radiosurgery is evolving and in select group of patients, this modality may be an appropriate single treatment for patients with 1-3 brain metastases or in select patients with 4 or more metastases (ABTA, 2016).

The introduction of stereotactic body radiation therapy (SBRT), or CyberKnife, opened up several new possibilities when it comes to finding the right treatment option for patients. While surgical resection is the standard care for many patients with non-small cell lung cancer, the location of the tumor and age and health status of patients with lung cancer often dictate whether they can undergo surgery. For those patients who are not surgical candidates, SBRT offers a cost and clinically effective outpatient and non-invasive therapy option. SBRT is also capable to treating localized prostate cancer, and pancreatic cancer (Bijani, 2013).

COST-EFFECTIVENESS

Upon numerous data comparisons, SRS and SBRT have demonstrated clinical value and economic sustainability, typically costing less in comparison to long-standing and well-accepted treatment options, with the added benefit of not having to make use of valuable inpatient resources. From a patient’s perspective, SRS and SBRT provide a patient-friendly treatment option compared to other treatment options such as conventional RT, especially those who live in a rural setting or a great distance from treatment centers. The treatment also allows patients to resume their daily activity as fast as possible (Bijlani, 2013).

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