A Comprehensive Investigation into the Application of

CyberKnife within Cancer Therapy

Physics for Biomedical Sciences, MDXXX

A Comprehensive Investigation into the Application of CyberKnife within Cancer Therapy 1

CyberKnife – An Extensive Review

Abstract

CyberKnife, a novel image-guided radiotherapy that relies upon the physical principle underlying

stereotactic radiosurgery as an alternative method for treating complex or inoperable tumors. The complex

three-dimensional imaging system targets cancer tissue and directs a focused beam of highly concentrated

photons to deform the DNA of tumor cells, thus triggering cell death. Evidence of the CyberKnife therapy

efficacy has pointed towards enhanced outcomes, particularly within recurrent or formerly irradiated cases.

As such, the aim of this essay, focuses on carrying out a mini-systematic review of current data, pertaining to

its underlying physical principle and biological application, its advantages, and limitations. Comprehensive

literature analysis was enacted utilizing several scientific databases, encompassing NCBI, PubMed,

ScienceDirect, ELSEVIER, OpenAthens, SpringerLink, and Google Scholar, with focus on the following

keywords: “CyberKnife” AND “Oncological applications” AND “Physical Principles” OR “Stereotactic

radiosurgery” OR “Non-invasive radiotherapy”. Data was selected and extracted based on the pre-

determined eligibility criteria to limit implicit biases and risk of research misinterpretation. The evaluation of

the CyberKnife has indicated a significant advantage within the high precision capability to target tumors,

minimizing damage to surrounding healthy organ tissue, whilst in real-time tumor detection. Unlike

conventional LINAC methods, leakage of radiation into surrounding healthy structures is significantly lower

when using the CyberKnife. As a result, it constitutes an invaluable technique for stereotactic radiosurgery

and tumor therapy. Nevertheless, it has its limitations, which include prolonged recovery time, insufficient

clinical research and testing, as well as dependence on CT imaging. In spite of that, it still marks a vital

milestone in cancer therapy development.

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A Comprehensive Investigation into the Application of CyberKnife within Cancer Therapy 2

Introduction

The CyberKnife (Figure 1), a non-invasive approach for treating cancer, through image-guided stereotactic

radiosurgery, in which X-ray and optical imaging systems are utilized to track in real-time, the targeted

tissue, in conjunction with accurately calibrated algorithms and the Coordinate Transformation Systems.(19)

Thereafter, a medical linear accelerator would deliver ionizing radiation in the form of X-ray beams, to target

the localized tissue.(18) Thus, relying on the interaction between the ionizing radiation and the tissue to

ablate and thus treat the identified range of tumors and certain non-malignant disorders (such as intracranial

and extracranial lesions), as an alternative to conventional surgical or radiation methods. (6,7,8,22)

Figure 1: Diagram of CyberKnife (Dimitriadis)

The CyberKnife has proven to be effective for the treatment of small, residual, inoperable, or previously

irradiated tumors. Which can be a suitable alternative to provide palliative treatment for patients who have a

poor prognosis.(27) Therefore, research of the CyberKnife and other forms of stereotactic radiotherapy

posits a crucial aspect of oncological therapeutic development, since the high degree of precision in tumor

therapy and minimal damage toward healthy tissue is a positive step towards reducing the vast impact of

cancer and improving the quality of life of patients during and after the procedure. (7,16)

This topic was selected due to evidence pointing towards improved disease control utilizing the CyberKnife

compared to conventional methods, hence making it an apt medical device for cancer therapy. This essay

will revolve around the physical principle, advantages, and disadvantages underlying the application of the

CyberKnife as a form of cancer therapy.

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A Comprehensive Investigation into the Application of CyberKnife within Cancer Therapy 3

Materials and Methods

Information Sources

The primary sources selected for this analysis of the CyberKnife were based on determining an eligibility

criterion which assisted in the selection of scientific literature focused on the fundamental principles

underlying stereotactic radiosurgery and how that relates towards the application of the CyberKnife,

particularly within cancer therapy. Therefore, appropriate keywords and search techniques were utilized to

filter a multitude of research papers, articles, and online books. This was conducted to depict relevant

information in relation to the underlying principle explaining how the CyberKnife operates and its

progression within the medical field. As such, the sources were specifically selected via a meticulous search

across major scientific databases, including NCBI, PubMed, ScienceDirect, ELSEVIER, OpenAthens,

SpringerLink, and Google Scholar. A total of 31 sources were selected for extensive review. The search

period was limited from 2005 to 2023 in order to focus specifically on the recent advances in stereotactic

radiosurgery and the CyberKnife, as well as concentrate on the more recent models of the CyberKnife

ranging from the G3 to S7.

Eligibility Criteria

A rigorous set of eligibility criteria were formulated in order to identify the resources that would formulate

the backbone of this essay, whilst maintaining objectivity and a lack of bias within the research. The

PICOTS framework was utilized to supplement the developed inclusion criteria, guaranteeing a well-chosen

source pool.

To begin with, the study characteristics were considered to determine the body of research chosen for this

systematic review. The chosen papers had to be fully accessible articles published in English to prevent

miscommunication resulting from errors in translation, as well as misinterpretations of data caused by

incompletely accessed articles. Certain publication types were excluded, such as surveys, individual case

reports, editorials, reviews, or commentaries, in order to impede the selection of more biased or subjective

papers. Instead, the chosen articles required precise relevance to the investigated therapy.

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A Comprehensive Investigation into the Application of CyberKnife within Cancer Therapy 4

As such, sources should involve the underlying physical principles, applications within cancer therapy,

development across the different models/years, and advantages or limitations posed compared to

conventional methods. Hence creating a more cohesive structure and systematic flow, since the information

collected is directly associated to the essay’s focus. The population of studies also concentrated on the effect

of the CyberKnife treatment on adult patients with malignant tumors. An additional governing factor for the

research on the general application of the CyberKnife treatment focused on cancer, while ruling out papers

on the treatment of lesions or other conditions.

A time-based requirement was also included within the exclusion criteria, whereby, resources analyzed must

have been published between 2005 to 2023. Thus, emphasizing the latest models of CyberKnife treatment

and reflecting up-to-date outcomes and trends within the field of stereotactic radiosurgery, upholding the

pertinence of this essay, whilst having a representative sample size for sufficient data collection. Moreover,

the selection necessitated the collection of resources from reputable databases, peer-reviewed journals, and

renowned publications, to ensure that the articles chosen had already undergone rigorous evaluation prior to

publishing, thereby validating the reliability of the references utilized. Within large scientific and medical

databases, the main keywords identified for the search consisted of: “CyberKnife” AND “Oncological

applications” AND “Physical Principles” OR “Stereotactic radiosurgery” OR “Non-invasive radiotherapy”.

Papers were filtered in order of relevance using the major prior mentioned databases. After narrowing down

the list of resources, abstract screening was conducted to further narrow the focus on the necessary

information and adhere to the eligibility criteria.

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A Comprehensive Investigation into the Application of CyberKnife within Cancer Therapy 5

Results

Physical Principles

The CyberKnife consists of two primary aspects, the 6-MV linear accelerator and the real-time imaging

system. The latter is contingent upon orthogonally arranged X-ray cameras, which capture in real-time

radiographs necessary for tumor targeting to compare to digitally recreated radiograph (DDR) cross sections

derived from the CT scan.(23) By positioning the digital radiograph to match the X-ray image, through

rotation or translation, the CyberKnife imaging software would orient itself to the location of the tumor.(19)

Utilizing the algorithm allows for continuous alignment between the imaging system and the patient, by

determining slight alterations within target position in less than a second with an uncertainty of ±0.5 mm.

This capability is exemplified within Figure 2. The robotic arm moves the linear accelerator within six

degrees of freedom (in the x, y, z planes) following the principle of stereotaxy for accurate tumor targeting,

as seen in Figure 3. (6,25)

Figure 2: Imaging diagram of CyberKnife Figure 3: Degree of freedom for CyberKnife

(Accuracy Incorporated) (Shepard)

Thereafter, the ionizing radiation is focused on the targeted tumor consisting of therapeutic X-rays, within

the energy range of higher than 105 eV.(29) After supplying the modulator with DC current, microseconds

long high-voltage pulses are generated. Within the diode-type electron gun, the temperature of the

conducting material (such as tungsten filament) will be increased, thereby producing electrons via

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A Comprehensive Investigation into the Application of CyberKnife within Cancer Therapy 6

thermionic emission. Afterwards, the released electrons will be pulse-injected and accelerated along the

waveguide toward the targeted tumor cells.

The magnetron within LINAC systems releases radio frequencies ranging from 30-kHz to 300-GHz. This

triggers microwave pulses through a high-power oscillator. The waveguide contains copper irises between

each cell, enabling electrons to travel along the waveguide and to assist in focusing the beam. To prevent

interference of the electron beam with other particles, a vacuum is created within the electron gun. This

electron beam is controlled by applying the effect of a magnetic field on electron movement. Utilizing two

sets of steering coils, and two sets of focusing coils, the electron beam is controlled and further focused into

a fine point, using the principle where the force direction applied on an accelerated path of electrons is at a

90° angle to the magnetic field and electron motion direction; according to the magnetic force and a moving

electric charge where the direction is determined by the Right-Hand-Rule: ⃑

F =q ⃑v × ⃑
B .(27,29) Thus, as the

electrons are accelerated within the LINAC system, they collide with a small tungsten or gold target,

generating high energy photons or X-rays. The deflection of the electrons as they move near a nucleus,

resultant from Coulomb attraction forces, compels the electrons to lose energy in the form of bremsstrahlung

radiation, generating X-rays in all directions. (3,29) This is modeled by the equation:

Ei −Ef =Photon Energy

The higher the atomic number of the targeted material, the larger the number of X-rays produced. Using a

primary collimator (comprised of tungsten), only forward-traveling X-rays are selected to pass through

producing a cone-shaped beam. The primary collimator plays an essential role in minimizing leakage of

radiation by absorbing scattered lateral X-rays. A flattening filter is applied where, the central part attenuates

more photons than the sides, generating a uniform distribution of photon beams. The shapes are further sub-

specialized via a multileaf collimator in order to best match the conformation of the tumor. As such the

primary principle of LINAC is depicted within Figures 4 and 5 below. (3,29)

Figure 4: Diagram of LINAC in CyberKnife Figure 5: Treatment Head Schematic (Chin)

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(Accuracy Incorporated)
A Comprehensive Investigation into the Application of CyberKnife within Cancer Therapy 7

Interactions with Human Tissue

The Guided Image System comprises of two ceiling-mounted X-ray sources and image detectors aligned

perpendicularly.(6) The System detects key structures within space, such as the skull, spine or implanted

gold markers called fiducial markers (FMs), which are small radiopaque objects that remain in constant

position post-implantation and are relative in space to both targeted and normal tissue. The Coordinate

System is defined by the positioning of the FMs, enabling the tumor to be targeted with minimal risk of

normal tissue irradiation. FMs must be synthesized from biologically inert metals, such as gold, that have

large atomic numbers for better visibility on X-ray images.(17) These captured X-ray images are then

compared with the DDR X-ray images, where the difference in the positioning of the patient is calculated.

The X-ray image produced by the CT scan relies on the different attenuations of tissues, dependent upon the

differing atomic numbers within the tissue, characterizing the varying shades in the CT image. As such,

when X-rays are propagated through the sample tissue, some of the photons are absorbed, whilst other

photons are transmitted to the detector. This is modeled by the equation I =I 0 e ∫

− μ ( x ) dx
, which describes the

attenuation of X-rays within inhomogeneous material like the human body.(5). Tumor tissue movement is

tracked within respiratory compensation using the image detection system that works in junction with the

optical markers attached to the synchrony vest worn by the patient, and delivers data on the tumor

positioning matching the patient breathing and movement.(6) This application of the CyberKnife imaging

Figure 6:
Example of
Imaging and
Tumor Targeting
for Meningioma
(Shepard)

system is exemplified within Figure 6 below:

Within the Stereotactic Body Radiation Therapy (SBRT), a considerable dose of ionizing radiation is

focused at the targeted tumor tissue. Interactions between the X-ray beam and human body occur at both a

cellular and atomic level. Photons in Radiosurgery interact with matter in three primary manners consisting

of photoelectric absorption, Compton scattering (the most significant within radiotherapy), and pair

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A Comprehensive Investigation into the Application of CyberKnife within Cancer Therapy 8

production. Accordingly, when exploring the effect of photons on human tissue, it is important to focus on

the effect on the individual atoms. Starting with the photoelectric effect, when a photon is absorbed by an

inner shell electron, it gives the electron sufficient energy to be ejected from the atom, most commonly for

the photon energy range up to 0.5 MeV. However, it must be noted that this is not considerably significant

within radiosurgery. As for Compton scattering, when a photon interacts with an electron, its energy is

absorbed, ejecting it from its orbit. Since the Compton scattering is dominant in the range between 200 keV

to 10 MeV, it is the most important interaction in medical applications, including imaging and radiotherapy.

Lastly, within Pair production, a photon transitions into an electron-positron pair, occurring mainly for

photons with energies more than 10 MeV. (3,29)

These highly focused X-ray beams damage the DNA, proteins and lipids of tumor cells via the stimulation of

free radicals and result in apoptosis, mitotic death, or permanently halting the growth of existing tumor

tissue. This phenomenon is observed within ablative treatment of complex spinal metastatic tumors, as an

example. Whereby, recent evidence expands upon the radiobiological effect of DNA damage, and includes:

tumor necrosis through vascular damage and antitumor immunity. Regional micrometasteses are expunged

and metastatic growth is suppressed through the “abscopal effect”. By altering the microenvironment

surrounding the tumor via radiation, a therapeutic effect isScattering

Figure 8: Compton realized, particularly since cancerous
Figure cells have a
10: Pair Production
Figure 7: Photoelectric Effect
(Chin) (Chin) (Chin)
higher sensitivity towards radiation compared to healthy cells. The concentration and energy of the X-ray

beams dictate the penetration depth, whilst the dose affects the pathophysiology of the cancerous tissue, as

witnessed in Figure 11. So, an increase in the concentration of ionizing radiation deposited within the tumor,

improves the CyberKnife therapy effectiveness. This is witnessed within the technique of hypofractionated

irradiation that directly damages the DNA double-strand (killing cells), and degrades the intratumor

microenvironment via microvascular deterioration and endothelial apoptosis causing tumor cell death.(1,7)

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A Comprehensive Investigation into the Application of CyberKnife within Cancer Therapy 9

Advantages and Disadvantages

Advantages

The CyberKnife has a multitude of advantages that give it an edge over conventional therapies for cancer

and other forms of stereotactic radiosurgery systems. In contrast to other forms of LINAC-based

radiotherapy, which have an accuracy range within millimeters, the CyberKnife accuracy range for tracking

tumor positions is within sub-millimeters. Therefore, if the accuracy of the pinpointed tumor is not

determined to be within a sub-millimeter range, a warning is given, and treatment is stopped. Consequently,

this aids in minimizing the risk of irradiating surrounding healthy tissue and enhances the accuracy of tumor

treatment. This accuracy is further verified by taking orthogonal X-ray images prior to each beam.

Furthermore, the high degree of precision targeting of tumors is maintained by the usage of the stereotactic

frame that determines the exact three-dimensional coordinates of the tumor, delivering the radiation exactly

toward the targeted area. This results in giving an edge towards CyberKnife over other conventional

therapies such as total body irradiation. The precision of the device is further fine-tuned by affixing small

circular collimators at the treatment head, further narrowing the X-ray beam compared to conventional

LINAC systems.(4,16,21)

Another irrefutable advantage of the CyberKnife is the flexibility of the robotic arm, where the arm’s six-

degrees of freedom enables the treatment of tumors across the body with a precise spatial awareness. As

such, in conjunction with the frameless robotic system, a consistent and controlled distribution of radiation

dose may be provided by the beams towards radiation-sensitive locations (e.g., tumors, irregular lesions,

etc.). As well as the application of real-time imaging and smart coordinate system, that further assists in real-

time organ positioning and optimization of radiation doses in contrast to other techniques.(4,16,21)

Certain treatment paths may use a non-isocentric approach and are the most appropriate treatment for

irregularly shaped large tumors and lesions. Accordingly, the CyberKnife solves the geometrical and

invasive limitations associated with frame-based stereotactic and gantry systems. Within the latter, CT

imaging was limited within the head, whilst in the former magnetic resonance systems were not initially

applied within the body. Since the CyberKnife is a minimally invasive procedure, patients experience less

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A Comprehensive Investigation into the Application of CyberKnife within Cancer Therapy 10

complications associated with surgery, since surgical trauma is eliminated, reducing swelling, tissue loss and

preventing post-op infection. Mortality risks associated with anesthesia are also eliminated. Even then,

inoperable tumors that were not completely resected during surgery, can be terminated or reduced via

CyberKnife treatment. Accordingly, the numerous advantages of CyberKnife therapy indicate its high degree

of versatility and efficacy within the field of stereotactic radiosurgery and non-invasive cancer therapy.

(4,16,21)

Disadvantages
In spite of the numerous advantages of the CyberKnife, it has few limitations. To begin with, the use of

hypofractionation that involves using larger fraction sizes than 8Gy, which, although participates in complete

tumor elimination and risk reduction of the tumor returning. Unfortunately, it also affects the high precision

usually associated with the CyberKnife, damages surrounding healthy tissue, and can also elevate risks of

late toxicity. This is due to the characteristic principle behind CyberKnife of “dose painting” requiring

smaller and more precise volumes. This disadvantage is supported by contemporary studies, in which

evidence suggests that large radiation doses from CyberKnife instigate endothelial cell damage and

contribute to microvascular dysfunction. Tumor cells that experience a low alpha/beta value correlate to an

improved benefit within the treatment. However, the same cannot be said regarding normal healthy tissue.

Whereby, such tissue experiencing the same lower alpha/beta ratio contribute towards injury, when exposed

to the high doses experienced within hypofractionation.(15)

Moreover, another significant limitation is the protracted treatment time ranging from thirty to sixty minutes.

Even then, the first indications of positive developments are also significantly prolonged, lasting up to 2-3

months post-irradiation, meaning that a patient must wait a lengthy duration for manifestations of treatment

efficacy. This recovery time can last even longer in other types of tumors. According to a study of patients

with prostate cancer who underwent CyberKnife therapy, radiation will remain with shifting levels of PSA

and indefinite tumor results, which could take months to years to fully disappear or could persist in the body

with halted growth. However, this uncertainty and worry can take a toll on the patient's well-being. The

requirement for repeated CT-scans is also a disadvantage as it gives out an extra dose of radiation that the

patient has to be subjected to. Additionally, clinical evidence is still insufficient, meaning that data on the

optimal dose-fractionation as well as optimal Planning Target Volume remain unknown. More clinical

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A Comprehensive Investigation into the Application of CyberKnife within Cancer Therapy 11

studies are required to optimally decide the dose-fractionation and to more accurately set PTVs.

Consequently, in spite of CyberKnife’s numerous advantages, its limitations must be rigorously investigated

and rectified in future development. (15,23,32)

Conclusion

To conclude, CyberKnife signifies a vital and encouraging future within the field of non-invasive

oncological treatment. Within this essay, the foundational physical principles underlying the CyberKnife and

Stereotactic radiosurgery were explored, focusing on the interactions between the photons and the biological

tissue, and how the imaging devices work in conjunction with the linear accelerator to specifically target

cancer, with minimal impact towards surrounding tissue, thus signifying it as an essential developing

standard within cancer management, particularly of difficult to operate/inoperable tumors. The advantages of

CyberKnife therapy were explored, such as the high degree of accuracy, which enables tumor pinpointing

with minimal healthy tissue damage, that is aided via the high degree of freedom within the robotic arm. In

addition, to the real-time positioning and monitoring of patient and tumor movement, for better tumor

targeting. Nevertheless, there were certain disadvantages that affected the efficacy of its application, for

instance, prolonged treatment times, and late manifestations, as well as unknown optimal dose-fractionation

and PTV. In spite of that, these disadvantages may be addressed by promoting increased clinical studies that

could contribute to enhancing understanding of core characteristics within CyberKnife therapy, and gather

more established trends regarding the impact of CyberKnife on different healthy and diseased tissue, to

determine improvements to these limitations.

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A Comprehensive Investigation into the Application of CyberKnife within Cancer Therapy 12

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