UNIVERSITY OF WISCONSIN-LA CROSSE

Graduate Studies

RAPID ARC VERSUS DYNAMIC CONFORMAL ARC STEREOTACTIC RADIOSURGERY

FOR INTRACRANIAL LESIONS

A Research Project Report Submitted in Partial Fulfillment of the Requirements for the Degree

of Master of Science in Medical Dosimetry

Angela Marie Kempen

College of Science & Health

Medical Dosimetry Program

August 2012

RAPID ARC VERSUS DYNAMIC CONFORMAL ARC STEREOTACTIC RADIOSURGERY

FOR INTRACRANIAL LESIONS

By Angela Marie Kempen

We recommend acceptance of this project report in partial fulfillment of the candidate’s

requirements for the degree of Master of Science in Medical Dosimetry

The candidate has met all of the project completion requirements.

______________________________________________________ _________________

Nishele Lenards, M.S. Date

Graduate Program Director

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The Graduate School

University of Wisconsin-La Crosse

La Crosse, WI

Author: Kempen, Angela M.

Title: Rapid Arc versus Dynamic Conformal Arc Stereotactic Radiosurgery for

Intracranial lesions

Graduate Degree/Major: MS Medical Dosimetry

Research Advisor: Nishele Lenards, M.S.

Month/Year: August 2012

Number of Pages: 34

Style Manual Used: AMA, 10th edition

Abstract

The aim of this study will be to dosimetrically evaluate dynamic conformal arc therapy

(DCAT) and volumetric modulated arc therapy (VMAT) via frameless, linear accelerator based

stereotactic radiosurgery (SRS) for the treatment of brain metastases.  Dosimetric evaluation

parameters will include the target coverage, conformity index, homogeneity index, gradient

index, integral brain dose and possibly a volume of the normal brain tissue receiving a certain

dose, which is yet to be determined.  Two plans will be developed per patient, with a total of five

to ten patients, utilizing DCAT and VMAT.  Results of this research will outline which planning

method may provide benefits or lack thereof depending on the brain metastases location, size,

and number of lesions, thus providing data in terms of conformity of target coverage as well as

lower dose spillage to rest of the brain.  This study will also provide dosimetric results regarding

advantages and disadvantages of forward versus inverse planning, in addition to the impact of

multileaf collimator (MLC) width size.

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Table of Contents

....................................................................................................................................................Page

Abstract............................................................................................................................................3

List of Tables.....................................................................................................................................

List of Figures....................................................................................................................................

Chapter I: Introduction....................................................................................................................5

Statement of the Problem.............................................................................................................9

Purpose of the Study....................................................................................................................9

Assumptions of the Study..........................................................................................................10

Definition of the Terms.............................................................................................................10

Limitations of the Study............................................................................................................13

Methodology..............................................................................................................................13

Chapter II: Literature Review........................................................................................................14

Chapter III: Methodology..............................................................................................................28

Subject Selection and Description.............................................................................................28

Instrumentation..........................................................................................................................28

Data Collection Procedures.......................................................................................................29

Data Analysis.............................................................................................................................30

Limitations.................................................................................................................................30

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Chapter I: Introduction

Brain tumors account for 1.5% of all malignancies diagnosed annually in the United

States.1 Approximately, 85-90% of central nervous system (CNS) tumors involve the brain,

whereas the spinal cord is involved in 20% of cases.2 According to the National Cancer Institute,

22,910 new cases of brain and other CNS tumors were diagnosed leading to 13,700 deaths in

2010.2 Brain tumors are the second leading cause of death in children, trailing behind leukemia.1

There are different classifications of tumors of the CNS; gliomas which include astrocytoma,

glioblastoma, glioblastoma multiforme, brainstem and thalamus tumors, in addition to pituitary,

medulloblastoma, oligodendroglioma, ependymoma, meningioma, lymphoma and schwannoma.1

Primary brain tumors are moderately uncommon; however, cerebral metastases occurs in

approximately one third of those diagnosed with cancer; therefore, making them the most

common brain lesion.1 The prognosis for brain tumors is not exceptionally good. However, the

5-year survival rates for patients with primary tumors has risen over the past couple decades to

an overall survival of 35%.1 Treatment for primary and metastatic brain tumors includes

surgery, chemotherapy, radiation therapy, immunotherapy and vaccine therapy.2 The options for

radiation therapy and chemotherapy vary depending on histology and anatomic location of the

brain lesion.2 Radiation therapy plays a major role in the treatment of patients diagnosed with

high-grade gliomas, including glioblastoma, anaplastic astrocytoma, anaplastic

oligodendroglioma, and anaplastic oligoastrocytoma, as well as those with brain metastases.

The origin of primary CNS tumors is currently unknown.1 Occupational and

environmental exposures, lifestyle and dietary factors, medical conditions and genetic factors are

all thought to perhaps have an association with brain tumors.1 The three most important

prognostic factors include age, performance status and tumor type.1 The incidence rate for CNS

tumors is 5 per 100,000 people.1 While age is the dominant variable in occurrence of these

tumors, race and gender also play a significant role. An increase in the incidence of CNS tumors

diagnosed in the elderly population has been noted.1 An increase in age expectancy, improved

availability and use of computed tomography (CT) and magnetic resonance imaging (MRI), as

well as increased knowledge and interest in improving quality of life in the elderly contribute to

the rise in incidence.1 The average age at diagnosis is 50 to 80.1 In 2008, approximately 21,810

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CNS tumors were diagnosed, with 16,400 of them being in the cerebrum.1 Of those, half were

diagnosed as gliomas, and 75% were high-grade gliomas.1

During recent years, radiation therapy has played a significant role in the treatment of

CNS tumors; therefore, increasing survival rates and improving quality of life.1 Patients

diagnosed with malignant tumors that cannot be surgically removed, are only partially excised,

or are associated with metastatic disease should undergo radiation therapy.1 Tumor type, tumor

grade, patterns of recurrence, and radioresponsiveness are important factors to consider in

determining the doses for radiation treatment.1 When determining total doses, the progression of

the tumor must be taken into consideration in addition to the potential risk of radiation necrosis

of normal tissues.1 Radiation therapy used in the treatment of brain tumors can be delivered in

multiple approaches. Consideration for the type of disease, tumor location and extent are

essential.1 Not only is a total resection of a brain tumor challenging, but obtaining adequate

resection margins in brain tissue is almost impossible with surgery alone.1 Therefore, radiation

therapy can be utilized after surgical procedures in an effort to prevent tumor recurrence.1 The

most common treatment technique is whole brain irradiation (WBRT), where the entire brain is

treated via opposing laterals. Additionally, this technique is commonly used in the presence of

brain metastases as well. Currently, standard treatment in the United States is 30 Gray (Gy) of

WBRT delivered in 10 fractions.19 A rapidly growing, important treatment option for patients

with CNS tumors is stereotactic radiosurgery (SRS). SRS is a technique utilizing radiation

treatments in a single, high-dose fraction of ionizing radiation that conforms to the shape of the

lesion.3 Radiobiology of such high dose fraction(s) needs to be well understood in terms of its

differences and possible benefits when compared to conventional fractionation of 180 to 200

cGy per fraction.

As briefly mentioned above, radiobiology is an important component in treating cancer

with radiation. Throughout history, accepted radiobiology has relied on the linear quadratic

model (LQ) which evaluates effectiveness of radiation delivery treatments by comparing daily

doses.5 Currently, typical clinical daily doses range from 1.2-2.5 Gy. Puck and Marcus6 showed

that fractional cell surviving radiation is equal to S.F. = e-(αΔ+βΔ2). This formula takes into account

the α/β ratio, which demonstrates differentiated dose response of late and acute responding

tissues. The ratio is low for late responding tissues and high for acute responding tissues.

Conventionally, it is the tolerance of late responding tissues within the field that limits the

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radiation dose.5 For tumor cells where the α/β ratio is low such as 2 Gy for melanoma, soft

tissue sarcoma, liposarcoma, prostate and breast, shortening the treatment time through

hypofractionation may be beneficial. In terms of radiobiology of hypofractionation, which is a

dose of 12-20 Gy per single fraction, the traditional behavior of the 4 R’s is altered.5 The 4 R’s

represent repair, re-assortment, re-oxygenation, and re-population. The new dominating role

players become bystander/abscopal factors, immune activation and tumor endothelium cell

deaths.5 Bystander/abscopal effects occur when unirradiated tumor cells behave as if radiated

due to the messages being carried out by radiated cells.5 These mitochondrial network

messengers are TNF- α, TRAIL, PAR-4 and ceramide.5 High dose radiotherapy may help

activate immune system response, which does not occur with conventional fractionation. Such

immune system response can help fight against the primary tumor as well as potentially prevent

distant metastases.5 At fractional doses of 10 Gy or higher, animal studies showed endothelial

cell death by activation of acidsphingomyelinase (ASMase) and ceramide generation.5 It is

important to note that endothelium in brain, lung and stomach are radio-resistant in the absence

of ASMase.5

With the radiobiology of SRS proven to be successful, various clinical studies have been

conducted to evaluate the efficacy of SRS for intracranial lesions. The most commonly treated

lesions with SRS include arteriovenous malformations (AVMs), vestibular schwannomas,

acoustic schwannomas, meningiomas, gliomas and metastatic brain tumors.4 Recently, there

have been studies showing strong evidence of the efficacy of SRS. University of Pittsburgh

Medical Center (UPMC) reported a study including 829 patients with vestibular schwannoma

who were treated with SRS to dose of 12-13 Gy.5 The results showed a 10 year control rate as

high as 97%.5 Studies performed evaluating SRS treatment of brain metastases either alone or in

addition to whole brain irradiation have shown improved local control. A trial on Radiation

Therapy Oncology Group (RTOG) 09-58 randomized 333 patients with 1-3 brain metastases (<4

centimeter diameter) and Karnofsky Performance Status (KPS) ≥ 70 to either WBRT alone

versus WBRT followed by an SRS boost.5 The results demonstrated significant improvement in

local control for all patients, in addition to improved survival rates for patients with a single

brain metastasis with WBRT followed by an SRS boost.5 There were two studies conducted by

UPMC evaluating treatment of meningiomas. The first study included 159 patients treated with

a median margin dose of 13 Gy.5 The results showed tumor control rates at 5 and 10 years both

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to be 93.1%.5 The second trial included 168 patients with petroclival meningiomas.5 The 5 and

10 year survival rates were 91% and 86% respectively.5

This technique has become a routine approach over the past couple decades. To

effectively acquire the benefits of SRS, high precision is vital. The treatment requires an overall

accuracy of approximately 1 millimeter (mm).3 SRS, historically, has referred to targeting

intracranial lesions, and it has been applied to a number of various benign and malignant

malformations, which can be delivered using various modalities. Different specialized

approaches for radiosurgery include Elekta’s GammaKnife, which utilizes a live Cobalt-60

source inside a gamma-ray treatment device, Accuray’s CyberKnife which is a particle beam

accelerator, or a medical linear accelerator with either a frame or frameless system using

BrainLab’s Novalis and OUR’s Rotating Gamma Unit.5 GammaKnife uses 201 very small well-

collimated beams of gamma radiation that focus precisely on the tumor. The patient has a

stereotactic frame attached to their skull, which is then attached to the automatic positioning

system. The patient is advanced into the machine and the shielded vault is closed for treatment.

CyberKnife utilizes a linear accelerator attached to a robotic arm with 6-degrees of freedom,

each of which delivers pencil beams of radiation. A medical linear accelerator can be adapted to

deliver SRS treatment. A linear accelerator system involves a gantry, which moves in space to

vary the delivery angle of a photon beam used for treatment. A stereotactic frame can be used,

however, more recently with the linear accelerator coupled with improved real-time imaging

methods, frameless systems have emerged. With MLC advancements and image-guidance

capabilities, linear accelerator based SRS has dramatically improved its accuracy and viability.

There are a few systems, from various manufacturers, being used in clinical application such as

Novalis (BrainLab, Heimstetten, Germany), Varian Medical Systems, and X-knife (Radionics,

Burlington, MA, USA).

For any type of SRS treatment, a vigorous immobilization is mandated. Historically,

linear accelerator based SRS required a stereotactic head frame, or halo, with a rigid fixation to

the skull. With recent advances in imaging modalities, more centers are utilizing the non-

invasive approach for patient comfort while maintaining similar accuracy as the rigid fixation

systems. Generally an aquaplast mask is used with a bite block for a non-invasive approach to

immobilization. An optical positioning system or image guidance tools such as on-board

imaging, cone beam CT, TomoTherapy, or Novalis ExacTrac may be used for position

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accuracy.5 The new dose delivery technologies, in addition to improved imaging capabilities,

have increased the use of precise stereotactic treatment delivery instead of conventional

fractionation.

Image guided radiation therapy (IGRT) techniques are required in order to achieve

stereotactic localization of the tumor.3 Linear accelerator based systems use secondary

collimation close to the patient. This shapes the beam while reducing penumbra.3 Penumbra is

analogous to radiation beam width; therefore, as penumbra becomes smaller, the dose falls off

quicker. Ideally, the smaller the penumbra, the more conformal the radiation field size becomes.

A multileaf collimator (MLC) can create off-axis beams. The MLC, with narrow leaves, is used

in a tertiary device even closer to the patient to further reduce penumbra.3 Dynamic delivery is

typically used with a large number of beams to irradiate the target. Intensity modulated radiation

therapy (IMRT), VMAT and DCAT are most commonly used with single isocenter, frameless,

linear accelerator based systems.

Over time, great advances have been made in regards to treatment techniques used to

deliver SRS. Multiple studies have proven the efficacy for this method of radiation treatment.

With the promise of SRS becoming such a prominent role in increasing overall survival rates, it

is essential to continue to study and evaluate the various treatment techniques in order to

continually improve treatment of brain lesions.

Statement of the Problem

There have been studies done evaluating the dosimetric differences between treatment

techniques used to deliver SRS for intracranial tumors.(8-16) Given that SRS is becoming such a

widely accepted treatment approach for intracranial tumors, it is essential to further investigate in

order to provide data on treatment techniques for SRS. With improved imaging technologies of

today, the popularity of non-invasive brain surgery is on the rise. There are multiple treatment

techniques that can be utilized for non-invasive linear accelerator based SRS, namely cone-

based, DCAT, IMRT, TomoTherapy and VMAT. One main difference between these delivery

methods is the planning, consisting of forward versus inverse. Secondly, with the advent of

smaller MLC leaf widths, it is expected that DCAT or VMAT may yield better dosimetric

results.16

Purpose of the Study

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The purpose of this research is to evaluate the dosimetric differences between treatment

plans using DCAT and VMAT. The plan comparisons include target coverage, conformity and

homogeneity index, integral brain dose, and gradient index. Between DCAT and VMAT, the

study aims to determine which technique offers a better planning evaluation index depending on

the brain metastases location, size, shape and number of lesions. This will in turn provide data in

terms of conformity of target coverage in addition to lower doses to the normal brain tissue.

Potentially the results of the study will indicate the most beneficial technique for delivery of SRS

treatments for intracranial tumors.

Assumptions

Although integral brain dose is a parameter that this research examines, per our radiation

oncologists we have also decided to track a volume of the normal brain tissue receiving a certain

dose, which is yet to be determined. This is an assumption in terms of clinical patient outcome.

Another assumption is in terms of the results of this research study. It is assumed that the DCAT

technique will produce slightly better results than RapidArc due to the use of non-coplanar

beams, which was concluded from multiple literature reviews.(8-15, 30-32) Otherwise, this research

does not have any other assumptions.

Definitions

Alpha/beta ratio. Term used in the LQ model. It is the dose where the number of cells

killed by the linear component α is equal to the cell kill from the quadratic component β. Early

responding tissues have a high ratio, whereas late responding tissues have a low ratio.7

Analytical Anisotropic Algorithm (AAA). A convolution-superposition algorithm used

to calculate radiation dose distribution.

Astrocytoma. Low grade or anaplastic tumors of the central nervous system. They

originate from the non-neuronal supporting cells.1

Computed tomography (CT). A diagnostic imaging modality, used in radiation therapy

treatment planning, that provides accurate information on tumor localization and identifying

dose-limiting structures.

Conformity index. According to Eclipse documentation, it is the volume closed by the

prescription isodose surface divided by the target volume.24

CyberKnife. A robotic radiosurgery system designed by Accuray.

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Dynamic conformal arc therapy (DCAT). A treatment technique in which MLC leaves

move to dynamically conform to the tumor outline during gantry rotation.

Ependymoma. Low or high grad tumors arising from the ependymal cells lining the

brain ventricles and central spinal canal.1

GammaKnife. A treatment machine utilizing Cobalt-60 gamma radiation for use in

radiosurgery of the head only. It is designed by Elekta.

Glioblastoma. A fast-growing type of central nervous system tumor. It arises from glial

(supportive) tissue of the brain and spinal cord and the cells have an appearance quite different

from normal cells. Also known as Glioblastoma Multiforme or grade IV astrocytoma.2

Gray (Gy). A unit of measured radiation dose. It is the absorption of one Joule (J) of

energy, in the form of ionizing radiation, per kilogram of matter.  (J/kg)

Homogeneity index. Target dose maximum divided by the volume of reference isodose.

Histology. The study of tissues and cells under a microscope.2

Image registration. Process where the images of the patient are aligned with respect to

the isocenter of the accelerator.1

Integral dose. The total energy absorbed by an organ(s) in terms of ionizing radiation,

expressed in gram-rads, also called volume dose, e.g. integral brain dose.

Intensity modulated radiation therapy (IMRT). A form of radiation treatment, where

the radiation field is divided into small “beamlets” via the aid of blocks/MLCs, and the intensity

of the beamlets is determined by planning optimization.

Isocenter. Point of intersection of the three axes of rotation (gantry, collimator, and

couch) of the treatment machine.1

Isodose lines. A radiation dose of equal intensity, e.g. 80% isodose line.

Linear accelerator. Radiation therapy treatment machine that accelerates electrons and

produces x-rays or electrons for treatment.1

Linear quadratic model (LQ). Method of demonstrating cell survival following

radiation with an equation. The equation approximates clonogenic survival data with a truncated

power series (second order polynomial) expansion of natural log of S (surviving proportion) as

follows:

lnS = -α x d – β x d2, where d = dose, α and β = expansion parameters.17

Lymphoma. Cancer that originates in cells of the immune system.2

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Medulloblastoma. Highly malignant cerebellar tumor with the tendency to spread via

the cerebrospinal fluid.1

Magnetic resonance imaging (MRI). A diagnostic, non-ionizing way to visualize

internal anatomy through a noninvasive technique. Imaging is based on the magnetic properties

of the hydrogen nuclei.1

Meningioma. A type of slow-growing tumor that forms in the meninges, which are the

thin layers of tissue covering the brain and spinal cord.2

Metastases. Spread of cancer beyond the primary site of origin.1

Monitor Unit (MU). A measurement of output on a linear accelerator used to deliver

radiation treatments.

Multileaf collimator (MLC). A secondary part of the linear accelerator that allows

treatment field shaping and blocking through the use of motorized leaves in the head of the

machine.1

Oligodendroglioma. A type of slow-growing tumor that forms in the oligodendrocytes,

which are the cells that cover and protect nerve cells in the brain and spinal cord.2

Penumbra. The region near the edge of the field margin where the dose falls off rapidly.

Width of the penumbra depends on the size of the radiation source, the distance from the source

to the distal part of the collimator, and the source-to-skin distance (SSD).18

Pituitary tumor. Being mostly benign, it is a cancer that forms in the pituitary gland,

which is a pea-sized organ at the base of the brain.2

Planning target volume (PTV). Volume that indicates the clinical target volume (CTV)

plus margins for geometric uncertainties, such as patient motion, beam penumbra, and treatment

setup differences.1

Schwannoma. Usually benign tumors of the peripheral nervous system that originate in

the nerve sheath, which is a protective covering.2

Stereotactic radiosurgery (SRS). Use of a high-energy photon beam with multiple

ports of entry convergent on the target volume.1

Thalamus. An area of the brain that helps process information from the senses and

transmit it to other areas of the brain.2

Target volume (TV). Area of a known and presumed tumor.1

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Volumetric modulated radiation therapy (VMAT). An innovative approach to

delivering IMRT via arcs where the gantry, MLC speed, and dose rate of the linear accelerator

may be modified via optimization.

Limitations

A limitation to this study is that it pertains only to brain tumors treated with stereotactic

radiation, and thus similar planning evaluation index may not apply to other tumor sites such as

lung or abdominal masses. The study will be conducted using 6 megavoltage (MV) beams for

all treatment plans. This can be considered a limitation since 15 MV will not be used and could

possibly provide a more conformal plan. Optimization parameters may be a limitation if the

same optimization objectives are used for each case. To date, most of the treatment planning

algorithms for SRS are still pencil-beam calculations (PBC) that do a very poor job for

heterogeneous mediums, such as brain tissue. Therefore, it is a limitation that the study utilizes

analytical anisotropic algorithm (AAA), as other algorithms will produce slightly different

results.

Methodology

This research compares and evaluates two separate linear accelerator based SRS

treatment techniques for intracranial lesions. The two treatment techniques that will be

compared include VMAT and DCAT. The study will compare a variety of dosimetric

parameters. The parameters that will be analyzed are target coverage, conformity index,

homogeneity index, integral brain dose and possibly a volume of the normal brain tissue

receiving a certain dose, which is yet to be determined.

Five to ten patients will be selected for this retrospective study. These patients will be

planned utilizing the Eclipse treatment planning system (TPS) (v10, Varian Medical Systems).

Two treatment plans will be created, one plan using VMAT, or RapidArc, and another plan using

DCAT. The plans will be constructed using the RTOG 95-08 guidelines for total dose,

dependent on maximum tumor diameter. The goal of the study is to determine whether or not

the treatment techniques generate comparable plans.

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Chapter II: Literature Review

Brain tumors account for 1.5% of all malignancies diagnosed annually in the United

States.1 Primary brain tumors are moderately uncommon; however, cerebral metastases occurs

in approximately one third of those diagnosed with cancer; therefore, making them the most

common brain lesion.1 The prognosis for brain tumors is not exceptionally good. However, the

5-year survival rates for patients with primary tumors has risen over the past couple decades to

an overall survival of 35%.1 Treatment for primary and metastatic brain tumors includes

surgery, chemotherapy, radiation therapy, immunotherapy and vaccine therapy.2 The options for

radiation therapy and chemotherapy vary depending on histology and anatomic location of the

brain lesion.2 Radiation therapy plays a major role in the treatment of patients diagnosed with

high-grade gliomas, including glioblastoma, anaplastic astrocytoma, anaplastic

oligodendroglioma, and anaplastic oligoastrocytoma, as well as those with brain metastases.

SRS is a treatment technique growing in popularity for the treatment of brain tumors.

There have been multiple studies done on increased survival and local control rates with SRS in

addition to external beam radiation therapy.5 Since studies are showing the efficacy of SRS, it is

important to understand the multiple modalities used to deliver these treatments, in addition to

possible dosimetric advantages of certain techniques. This review of literature will cover topics

such as a variety of dosimetric parameters used to analyze multiple treatment planning

techniques, effects of radiobiology and effects of calculation grid sizes.

A book on hypofractionation, written by Pollack and Ahmed5 described multiple

intracranial tumors treated with SRS and the advantages of this type of treatment. Additionally,

the dose selections and tumor control rates were studied and reported.5 With SRS, delivering

high doses and conformity is possible, while effectively sparing critical structures adjacent to a

tumor volume from radiation-induced toxicities.5 The book mentioned several specific studies

and RTOG protocols specific to meningioma, vestibular schwannoma (VS), glomus tumor,

pituitary adenoma, craniopharyngioma, chordoma, chondrasarcoma, and brain metastases.5

Regarding meningiomas, studies were conducted at Mayo Clinic and UPMC, which showed

increased tumor control rates with 12-18 Gy SRS.5 Studies done with VS at UPMC giving 12-13

Gy SRS yielded 10-year tumor control rates of 97%.5 A UCSF study treated glomus jugulare

with SRS and had a tumor control rate of 95% with a mean follow-up of 71 months.5 Johns

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Hopkins found linac-based SRS to have the same control rate of 95%.5 Pituitarty ademonas

treated with SRS had excellent tumor control rates of 92-100%; however, endocrine cure rates

were reported lower.5 There were inconsistencies of the endpoints used in varying studies, but

an average endocrine cure rate was approximately 20-30%.5 For patients with

craniopharyngiomas treated with 11.5 Gy SRS in a study from Japan, tumor control rates were

reported at 79.6%.5 UPMC treated with 13 Gy SRS and found the 1, 3, and 5-year overall local

control rates were 91%, 81%, and 68% respectively.5 Mayo Clinic studies involving skull base

chordomas treated with SRS to a marginal dose of 15 Gy had 2 and 5-year survival rates of 89%

and 32% respectively, with a follow-up time of 4.8 years.5 A dose of 16 Gy SRS was reported at

UPMC to yield a 5-year actuarial local tumor control rate of 62.9%.5

Brain metastases have historically been treated with whole brain radiation therapy

(WBRT); however, numerous RTOG protocols and randomized trials have utilized SRS for

selected patients with brain mets.5 A trial at the University of Pittsburg showed the median

survival for WBRT + SRS increased to 11 months versus 7.5 months for WBRT alone.5 While a

phase III study from MD Anderson showed patients with SRS + WBRT also demonstrating

increased survival rates, they also unfortunately found they were significantly more likely to

show decline then patients assigned to SRS alone.5

One of the most feared complications of brain radiotherapy is optic neuropathy. Utilizing

SRS to treat skull base tumors has shown a low incidence of this occurance.5 Mayo Clinic

showed that the risk of developing clinically significant radiation-induced optic neuropathy was

1.1% for patients receiving a single SRS dose of 12 Gy or less.5 In addition, vascular damage

from SRS is rare as well. In order to decrease vascular damage, it is recommended that the

prescribed dose cover less than 50% of the diameter of the internal carotid artery or the

maximum dose to the internal carotid artery be limited to 30 Gy or less.5 Damage to the

brainstem has low occurrence also. According to Quantitative Analyses of Normal Tissue

Effects in the Clinic (QUANTEC), the tolerance of brainstem to a single dose of radiation, based

on a maximum dose, is 12.5 Gy.5

A study similar to those reviewed in the book mentioned above was conducted by Mehta,

Tsao, Whelan, et al.7 The researchers systematically reviewed evidence for the use of SRS in

patients diagnosed with brain metastases. Key clinical questions were addressed comparing a

radiosurgery boost with whole brain radiotherapy to whole brain irradiation alone. The outcomes

15

considered overall survival, quality of life or symptom control, brain tumor control or response,

and toxicity.7 Multiple databases were searched and reviewed from 1990-2004 to collect data

regarding the role of radiosurgery for brain metastases.7 This data was tabulated to create an

evidence-based review, which included an assessment of the level of evidence. The review

evaluated three randomized trials regarding newly diagnosed brain metastases. Level I evidence

indicated that overall survival does improve for patients with a single brain metastasis, and that

local brain control was significantly improved in those patients with one to four metastases.7 At

6 months after treatment, one trial demonstrated decreased steroid dosage and improvement of

KPS; however, a non-significant increase in the risk of toxicity was noted.7 Evidence from two

randomized trials, two prospective cohort studies, and 16 retrospective series indicated that

radiosurgery alone as the initial treatment did not alter overall survival in patients.7 It was noted

that utilizing radiosurgery at the time of progressive or recurrent brain metastases requires

stronger evidence.

Similar to the evidence-based reviews conducted by Mehta, Tsao, Whelan, et al7, data

was collected from 10 different institutions by Sneed, Suh, Goetsch, et al.25 The researchers

quantitatively compared survival probabilities for 569 patients with newly diagnosed brain

metastases. 268 patients initially underwent radiosurgery alone, which was assessed in

comparison to 301 patients who were managed with radiosurgery plus whole brain irradiation.25

One of the trials completed by Pirzkall, et al reviewed 236 patients with 1-3 brain metastases and

KPS ≥ 50.25 The trial demonstrated that patients with no known extracranial disease had a

median survival time of 15.4 months when managed with radiosurgery plus whole brain

irradiation versus 8.3 months survival time when treated with radiosurgery alone.25 However, a

similar study looking at 105 patients performed by Sneed, et al showed no survival difference.25

Regarding salvage therapy, it was determined that more data needs to be collected from

prospective trials following patients being treated with salvage therapy.25

In addition to the above-mentioned articles, the American College of Radiology

conducted a study looking at multiple trials and clinical scenarios regarding treatment for brain

metastases.26 It was found that the median survival for a patient with brain metastases varies

between 4 to 6 months after WBRT, which is an established standard of care for most patients

diagnosed with brain metastases.26 Many different dose schemes and fractionations, as well as

various total doses have been studied, however, none of the regimens have proven better than

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another in terms of survival or efficacy.26 30 Gy in 10 fractions or 37.5 Gy in 15 fractions are

most commonly used and have proven to be an effective palliative treatment for brain

metastases.26 A majority of patients who receive WBRT do not receive local control, although

approximately half of these patients do experience an improvement in neurologic symptoms.26

The multiple studies reviewed did show the effectiveness of SRS, however, this may be related

to choosing an appropriate patient selection. It was also stated that SRS alone probably couldn’t

replace the benefits of WBRT.26

The above articles discussed all explain treating brain metastases with a high dose in a

single or very few fractions. Treating with high dose schemes requires careful consideration

since the risk of damage to normal tissues associated with this type of treatment increases with

increased dose. Nedzi27 reviewed radiation treatment courses using dose per fraction schemes of

10 Gy or above. He evaluated the efficacy and safety of such high doses, also known as ablative

therapy. Many disease sites were reviewed, including trigeminal neuralgia, epilepsy,

arteriovenous malformations, acoustic neuromas, meningiomas, pituitary adenomas, malignant

tumors including early stag lung cancer, brain metastases, and liver and spine metastases. High

rates of recurrence are noted if complete resection of meningiomas is not achieved and

unfortunately a variety of meningiomas can be challenging to completely surgically resect due

the location of the tumor.27 In a situation such as this, SRS can be extremely effective.

Retrospective data of small meningiomas that could not under go surgery supported an 89% to

94% progression-free effect for patients treated with 15 to 16 Gy radiosurgery.27 Prospective

trials are needed to evaluate the efficacy of SRS with pituitary adenomas.27 Evaluation of two

retrospective studies identifying patients with multiple brain metastases treated with WBRT ±

SRS showed that SRS added to WBRT has benefits.27 The addition of SRS improves

performance status and survival; however, because these patients do not have long-term survival,

more data is required on quality of life during the end of the patients living days.27 Liver and

spine metastases have been studied with SRT, a promising treatment method requiring extra

precise planning due to the proximity to crucial adjacent structures.27 Specific critical organ dose

tolerances specific to ablative therapies must be carefully followed in any radiosurgery

treatment.

The decision to treat a patient diagnosed with brain metastases is often influenced by a

variety of considerations. One factor frequently considered is whether a SRS program is readily

17

available to the institution where a patient is treated. A multi-institutional study of factors

influencing the use of SRS for brain metastases was recently conducted by Hodgson,

Charpentier, Cisgar, et al28. Because the implementation of SRS is technically complex, this

study chose to look at how local availability of SRS affected how patients diagnosed with brain

metastases were treated. 973 randomized patients were chosen, and logistic regression analyses

were performed.28 This analysis indicated factors associated with using SRS as a boost treatment

in combination with WBRT. Of these patients, SRS was given as a boost treatment to 70, which

was approximately 7.8% of the randomized population.28 The analysis showed the factors most

significantly influencing the use of SRS treatment were fewer brain metastases, controlled

extracranial disease, age, and the availability of an onsite SRS program at the hospital or clinic

where the patient was being treated.28 Results showed that whether or not the institution offered

SRS changed the percentage of patient receiving SRS drastically, especially for patients with 1-3

brain metastases, good performance status, and no evidence of extracranial disease.28 For

facilities that did not have a SRS program, 3.0% of patients underwent SRS treatment, versus

40.3% of patients who were treated at a facility with an onsite SRS program.28

With multiple factors influencing treatment decisions for patient diagnosed with brain

metastases as mentioned above, Sperduto, Berkey, Gaspar, Mehta, and Curran29 conducted a

study to introduce a new prognostic index for patients with brain metastases. They looked at

1,960 patients in the RTOG database and compared the new prognostic index with three other

indices.29 Advantages and disadvantages were found with all four indices compared. However,

Recursive Partitioning Analysis (RPA) and the new Graded Prognostic Assessment (GPA) had

the most statistically significant differences, with the GPA being the least subjective and most

quantitative.29 GPA along with (Score Index for Radiosurgery) SIR incorporated the number of

brain metastases, whereas RPA and Basic Score for Brain Metastases (BSBM) did not include

this parameter.29 SIR requires calculation of the volume of the largest lesion, which varies

depending on the treatment system used.29 With varying systems, it is often only assessed at the

time of treatment planning.29 This study was important in determining which treatment approach

is most appropriate for a given patient. Determining the appropriate treatments are crucial to a

patient’s outcome, and a useful prognostic index could guide the decisions made and presented

by physicians and their colleagues.

18

Because of its precision and high dosage, SRS is becoming more and more utilized in the

treatment of intracranial tumors. Researchers have conducted several studies, which have

compared and evaluated the dosimetric differences between linear accelerator based stereotactic

radiosurgery.(8-15, 30-32) The various techniques include three dimensional conformal radiation

therapy (3D-CRT), IMRT, DCAT, and VMAT (RapidArc), in addition to CyberKnife and

GammaKnife. The dosimetric comparisons included target coverage, conformality index,

heterogeneity index, and dose received by critical structures proximal to the tumor. (8-15, 30-32)

Ding, Newman, and Kavanagh et al8 looked at dosimetric comparisons of different

treatment techniques, including 3D-CRT, DCAT, and IMRT for the treatment of brain tumors. In

this study, fifteen patients were selected who had been treated with Novalis.8 For all patients,

3D-CRT, DCAT and IMRT plans were done.8 A standard margin of 1mm was used for the

planning target volume (PTV) and 90% was used as the prescription isodose line for all plans.8

In order to quantify comparisons made in the study, the target coverage at the prescription dose,

conformity index (CI), and heterogeneity index (HI) were analyzed.8 For PTVs ranging in size

from ≤ 2 cm3 to ≤100 cm3, IMRT plans yielded a high CI. IMRT plans had better target

coverage at the prescription dose, in addition to a better HI for medium sized tumors.8 For large

tumors with PTV >100 cm3, the IMRT plans demonstrated good target coverage at the

prescription dose and HI and CI values were comparable to those values found with the 3D-CRT

and DCAT plans.8 IMRT utilizes inverse planning which is better for overlapping of the target

and critical structures. It also lends the ability to decrease the dose to normal brain tissue.8

IMRT was not recommended for small tumors; however, for large tumors IMRT was superior.8

DCAT was suitable for most treatments of brain tumors, and showed improved coverage of the

treatment volume when used for larger tumors.8 The plans produce high conformity, and the

treatment can be delivered in less time than 3D-CRT treatment plans. 3D-CRT was useful for

small tumors because it demonstrated increased ability to conform the dose distribution to

irregular target shapes.8

Solberg, Boedeker, and Fogg et al9 compared absolute dose distributions from three

radiosurgery delivery techniques, including conventional approach using non-coplanar circular

arcs, static field conformal treatment, and dynamic arc field shaping. A simulated target with

three overlapping spheres was used for straightforward planning. The tumors ranged in size and

required different numbers of isocenters.9 The study found that circular arc techniques required

19

multiple isocenters for the treatment of large, which in this case was 9.79 cm3, or irregularly

shaped tumors resulting in very low homogeneity within the target volume.9 The single isocenter

approach used with both the static fields and dynamic conformal arcs, increased the homogeneity

within the target volume and decreased the dose to surrounding critical structures.9

Hazard, Wang, and Skidmore et al10 assessed the conformity of DCAT treatments for

SRS delivered on a linear accelerator.10 174 cases were studied and quantitatively compared

looking at the target volume, and prescription isodose volume, which is defined as the total

volume encompassed by the prescription isodose surface.10 The 3 mm MLC improved

conformity by the ability to shape the MLC pattern to the beams eye view of the target volume

for each 10 degrees of the arc.10 The resulting CI’s closely compared to that of GammaKnife

treatment plans.10 Treatment times with DCAT are less than with GammaKnife as well. In

addition, because conformity varies with different prescription isodose surfaces, the researchers

chose a uniform method for selection of this surface.10 It was required that 95% of the target

volume receive 100% of the dose, in addition to 99% of the target volume receiving 95% of the

dose.10 It is crucial to achieve high dose coverage to the target volume by the prescription

isodose surface, as well as decrease complications by minimizing the volume of normal tissue

receiving minimal dose.

Wang, Kirkpatrick, and Chang11 analyzed coplanar and non-coplanar arc treatments using

intensity modulated arc therapy (IMAT). Patients included in the study were diagnosed with 2 to

5 lesions. A Novalis TX linear accelerator with high-definition MLC was used to deliver the

treatments.11 The MLC leaf width was 2.5 mm at isocenter. Treatment planning was done

utilizing RapidArc and the study compared the effects of a single arc versus 5-arcs on IMAT

SRS treatment plans.11 The target coverage, CI and volume of tissue within the low dose isodose

line of 5 Gy were compared.11 It was concluded that 5-arc non-coplanar treatment plans were

superior regarding CI and volume of tissue within the 5 Gy isodose line.11 The 5-arc plans

produced a smaller volume within the 5 Gy isodose line in addition to higher conformality.11

Lo12, at Standford University Medical Center, evaluated the quality of brain SRS

treatment plans between CyberKnife from Accuray and RapidArc from Varian.12 CyberKnife is

a non-isocentric, cone-based SRS system utilizing 6 MV, which has the ability to generate

isodose distributions with a high conformity index and rapid dose fall off.12 RapidArc is MLC

based volumetric modulated arc therapy. With 2.5 mm high-definition (HD) MLC, the treatment

20

planning system can design the potential isodose distributions required for brain SRS.12

CyberKnife treatment plans were recreated using RapidArc with the same target coverage and

dose constraints.12 The results of the study yielded superior plans created when using

CyberKnife.12 The RapidArc treatment plans were found to have higher CI by 10%, a 70%

higher ratio of volume getting 50% of the prescription dose to a volume receiving the

prescription dose, 50% of the brainstem receiving more than 8 Gray (Gy), and 45% higher dose 2

cm from the target on average.12

A study reviewing the feasibility of single-isocenter VMAT SRS for multiple brain

metastases was reported by Clark, Popple, Young and Fiveash13. The study looked at the plan

quality of single versus multiple isocenter VMAT planning technique using Varian RapidArc

technology.13 The treatment plans were created using single-arc/single isocenter, triple-arc (non-

coplanar)/single isocenter, and triple-arc (coplanar)/triple isocenter arrangements.13 Each patient

had three brain metastases. In using Paddick and RTOG evaluation tools, plans were

quantitatively evaluated with dosimetric parameters including conformity index scores, gradient

index scores and 12 Gy isodose volumes.13 As a result, all three plans were clinically acceptable;

however, non-coplanar arcs showed small improvements in the conformity index as well as

smaller 12 Gy isodose volumes when the three metastases were in close proximity to each

other.12 When the lesions increased distance between them, only small differences were

observed.12 The study concluded that a single isocenter can be used to deliver plans with

equivalent conformity to the multiple isocenter plans.

A study was conducted by Mayo, Ding and Addesa, et al14 evaluating intracranial

stereotactic radiotherapy (SRT). It was the initial experience delivering linear accelerator based,

frameless SRT with RapidArc. The treatment plans were created using 2-3 arcs per isocenter, in

addition to at least one of the arcs being non-coplanar.14 The study compared a few dosimetric

parameters including conformity, homogeneity within the tumor volume, dose gradient and

treatment times.14 The results showed comparable outcomes with other treatment techniques such

as CyberKnife, TomoTherapy and static-beam IMRT. In addition, treatment times ranged from

4-7 minutes, which is considerably shorter than other techniques. Therefore, it was concluded

that SRT using volumetric IMRT with RapidArc is a viable alternative.14

Similar to the study conducted by Mayo, Ding, and Addesa, et al14, was a study

conducted by Yang, Zhao, Li et al15. They investigated the feasibility of RapidArc for SRS and

21

SRT for the treatment of intracranial lesions. Ten patients were studied that had previously been

treated with conventional DCAT plans. The patients were replanned with RapidArc utilizing

multiple non-coplanar arcs along with a single arc.15 The plan quality was evaluated by

comparing conformity and homogeneity indexes as well as the volumes of normal tissue

receiving low doses (V50, V25 and V10) of radiation between the RapidArc linear accelerator

based with DCAT.15 The volumes of normal brain receiving 50%, 25% and 10% of the dose

increased with the single arc RapidArc treatment plans.15 Increased MU’s were found with the

RapidArc plans; however, treatment time was comparable to DCAT.15 The results yielded

RapidArc superior when multiple arcs were implemented.15

Lagerwaard, Verbakel, van der Hoorn, Slotman, and Senan30 conducted a study

evaluating a single arc utilizing RapidArc treatment for SRS. A single arc can be delivered in

less than 10 minutes, which is beneficial to both patients and the staff in radiation therapy

departments.30 SRS in addition to WBRT is an established treatment option for patients who are

diagnosed with a limited number of brain metastases. Most SRS treatments are delivered in a

time frame of 20 minutes up to an hour depending on the number of lesions.30 The researchers

were evaluating whether one arc using RapidArc could possibly lessen the treatment duration.

For this study, RapidArc treatments were created for six patients with between 2 and 8 brain

lesions.30 The volumes of these lesions ranged from 1.0 to 37.5 cm3.30 All the lesions were

treated to 18 Gy and prescribed to the 80% isodose line.30 The single arc RapidArc plans were

compared to 4-5 conventional dynamic conformal arcs using CI and DVH’s. The results of this

study found the CI of the RapidArc plans to be superior to the dynamic conformal arcs.30

RapidArc yielded a CI of 1.5 ± 0.6 versus 2.1 ± 0.7 for dynamic conformal arcs.30 The RapidArc

plans also had a decreased volume of normal brain tissue encompassed in the 80% isodose

surface.30 In addition, the RapidArc plans resulted in a drastic decrease in treatment delivery

times, averaging 8 minutes to deliver each treatment.30 In conclusion, RapidArc can be regarded

as an effective way to deliver SRS treatments in addition to WBRT.30

A few studies focused on specific intracranial lesions and compared different treatment

techniques using SRS. Lee, Chao, Wang, et al31 conducted a study on vestibular schwannomas

using DCAT with the Novalis system and Tomotherapy. They compared the dosimetric results

of these treatment methods using conformity index, homogeneity index, comprehensive quality

index for nine critical structures, gradient score index, and plan quality index. 10 to 16 Gy was

22

prescribed to PTV volumes ranging from 0.27 – 19.99 cm3.31 The study found Tomotherapy

conformed better to the PTV but had a decreased gradient score index.31 Tomotherapy also

showed an advantage over DCAT with a better plan quality index; however, the radiation beam

was on longer and more monitor units were used to deliver the treatment.31 The study confirmed

more research should be conducted to determine whether the dosimetric advantage of

Tomotherapy confirms a clinical benefit as well.31

Grabenbauer, Ernst-Stecken, Schneider, et al32 evaluated different techniques for SRS of

pituitary adenomas. Out of 152 SRS procedures, ten patients with pituitary adenomas were

compared using conformal, DCAT with mMLC, circular collimators, and 8-10 conformal static

mMLC beams with and without IMRT.32 The prescribed total dose used was 18 Gy, with Dmax of

the optic chiasm <8Gy, and <10mL of the temporal lobe receiving 10Gy.32 The dosimetric

parameters the researchers chose to compare the plans were coverage, CI, HI, and the volume of

the temporal lobe receiving 10Gy.32 IMRT had better coverage in 5 out of 10 patients over

DCAT.32 In addition, IMRT had a smaller volume of tissue outside the PTV receiving >18Gy in

9 of 10 patients.32 One patient had better conformity with circular collimators.32 Circular arcs,

however, yielded the highest maximum dose of 39.8 Gy, which produced a HI of 2.2 versus HI

of 1.13-1.2 for the other treatment techniques.32 The study concluded that IMRT techniques are

safe and appropriate for SRS of pituitary adenomas.32

The treatment modalities mentioned above have been compared in many of the studies

quantitatively by utilizing a variety of dosimetric parameters. CI was a common parameter

assessed; however, there are multiple formulas used to calculate CI. Feuvret, Noel, Mazeron,

and Bey33 analyzed and evaluated conformity indices based on their field of application.

Dosimetry treatment planning systems provide dose distribution for each CT slice and dose-

volume histograms (DVH) to aid in analyzing treatment plans, but there is no indication of

conformity.33 A conformity index (CI) can be helpful by providing a quantitative score in order

to compare several treatment plans for the same patient.33 The CI was primarily developed for

SRS treatment plans, and integrates multiple parameters.33 There are several volume-based

conformity indices in various clinical settings including RTOG, Saint-Anne, Lariboisiere, Tenon

( SALT), Lomax and Scheib, van’t Riet et al, and Baltas et al.33 For SRS, RTOG based its CI on

several parameters, including reference isodose values of the treatment plan, reference isodose

volume or prescription isodose, and the target volume.33 Ideal CI equals 1, while a index greater

23

than 1 indicates the irradiated volume is greater than the target volume and extends into normal

structures. A CI less than 1 indicates the target volume is only partially irradiated.33 As defined

by RTOG, when a CI value is between 1 and 2, the treatment complies with guidelines, if the

index falls between 2 and 2.5, or 0.9 and 1 it is a minor violation, and values less than 0.9 or

greater than 2.5 are considered major violations.33 The disadvantage to this CI is it does not

consider the degree of spatial intersection of two volumes or their shape.33 An ideal CI is yet to

be determined in order to achieve the desired objective of the CI, which is to quantify the quality

of treatment with 100% specificity and sensitivity.33

The conformity of linear accelerator-based SRS using DCAT was assessed by Hazard,

Wang, Skidmore, et al34 in a research study. In addition, the researchers also evaluated and

described a standardized method of isodose surface selection.34 The CI at the prescription

isodose surface of 174 targets were calculated.34 A prescription dose was chosen using the

following criteria: 95% of the target volume encompassed by the prescription isodose volume

and 99% of the target volume encompassed by 95% of the prescription dose.34 It was found that

median CI was 1.63 at the prescription isodose surface and 1.47 at the “standardized”

prescription isodose surface.34 The CI values previously reported for Gamma Knife SRS were

similar to the CI found in this study looking at linear accelerator-based SRS.34 A “standardized”

prescription isodose surface may aid physicians in choosing a prescription isodose surface that

takes into consideration coverage and conformity, thus helping with CI comparison.34

Wagner, Bova, Friedman, et al35 presented a simple way to compare SRS plans. The

purpose of the index evaluated was to gauge multiple competing SRS plans, but not necessarily

to assess the superiority of one method of treatment delivery over another.35 The researchers

provided a combined conformity/gradient index (CGI), which is an average of a conformity

score and gradient score. Only three pieces of data were required to compute this relatively

simple index.35 This includes the total volume irradiated to the prescription isodose level, the

target volume, and the total volume irradiated at 50% of the prescription isodose level.35 A

limitation of the CGI score is its inability to consider the issue of dose inhomogeneity within the

tumor volume.35 Another limitation is that the CGI does not assess radiation dose to

radiosensitive structures beyond normal brain tissue.35 Therefore, it is concluded that the CGI is

a very simple tool to calculate for homogenous lesions that are located away from radiosensitive

24

structures.35 The CGI tool was proven useful a as simple, quick calculation for “forward”

planning as well as “inverse” radiosurgery planning.35

The studies reviewed previously included multiple treatment techniques including

Gammaknife and Cyberknife, in addition to techniques utilized for non-invasive linear

accelerator based SRS, namely cone-based, DCAT, IMRT, TomoTherapy and VMAT. One

main difference between these delivery methods was the planning, which was forward versus

inverse. Another comparison that has been analyzed includes the MLC utilized in treatment

delivery. With the introduction of smaller MLC leaf widths, it is expected that DCAT or VMAT

may yield better dosimetric results.16 Chern, Leavitt, Jensen et al16 performed a dosimetric

comparison of BrainLAB micro-MLC with the leaf widths being 3 mm, 4.5 mm and 5.5 mm and

Varian Millennium MLC with leaf widths of 5 mm and 10 mm.16 For dynamic conformal arc

stereotactic radiosurgery for treatment of intracranial lesions, it was assumed that the micro-

MLC would yield further improvement in target conformity and normal tissue sparing.16 Two

plans were done for each of the 23 patients in the study, one using the minimal 3 mm MLC and

one using the minimal 5mm MLC, while keeping all parameters the same except for collimator

angle, which were optimized for each arc in the separate plans.16 In order to evaluate the normal

tissue sparing in close proximity to the target volume, a peritumoral rind structure of 1cm was

created. The conformity index used was an equation described by Paddick, as used in a few

other studies.16 The conformity index and normal tissue sparing was found to be slightly

improved with the minimal 3 mm MLC.16 In conclusion, the 3 mm micro-MLC provided small

improvements with better target coverage and increased normal tissue sparing with SRS utilizing

DCAT.16

Similarly, a dosimetric study was completed by Jin, Yin, Ryu, Ajlouni, and Kim36 using

different leaf-width MLCs for treatment planning with DCAT and IMRT. 3 mm micro MLC, 5

mm MLC, and a 10 mm MLC were evaluated for SRS using the Brainscan treatment planning

system.36 The dosimetric analysis used for comparison of the treatment techniques, target

volumes, and treatment sites included CI, DVH for organs-at-risk, and the percentage target

coverage.36 When using DCAT, significant differences were found between the different leaf-

width MLCs.36 The CI ratio depends on the size of the target volume, and targets approximately

1 cm3 showed a large variation between CI, however, for relatively large targets over 8 cm3, the

variation decreased.36 For IMRT plans, the results demonstrated the CI with minimal difference

25

between different MLC leaf widths.36 For both treatment planning techniques, the 3 mm MLC

showed improved organs-at-risk DVHs, more notable with the organs-at-risk with smaller

volumes.36 The study concluded that narrower leaf-width MLC could have some advantages

over wider leaf-width MLC.36

Monk, Perks, Doughty and Plowman37 conducted a study comparable to Jin, Yin, Ryu,

Ajlouni, and Kim regarding a comparison of different leaf-width MLCs. 3 mm MLC and 5 mm

MLC were dosimetrically compared on a linear accelerator for SRT treatment of intracranial

lesions. Fourteen patients diagnosed with brain metastases, who had previously been treated

with BrainLAB’s 3 mm micro MLC were replanned using the 5 mm Varian Millennium MLC.37

The same target coverage was achieved by adjusting the MLC shape to conform around the

PTV; however, noncoplanar beam arrangements were used.37 The results found that the 5 mm

Varian Millennium MLC provided an increase in the conformity index.37 The DVH curves

showed an increase in the volume of normal tissues receiving low dose radiation, but the

maximum dose to critical structures did not significantly increase with the 5 mm MLC.37 It was

concluded that the 3 mm micro MLC does consistently improve PTV conformity and achieves

decreased low dose spillage to surrounding normal tissues.37 However, quantitatively the

improvements are not significant enough to give evidence of one leaf-width MLC to be more

beneficial than the other.37

In addition to treatment delivery methods, radiobiology is an important component of

treating cancer with radiation. The radiobiological rationales of SRS are essential, and currently

the radiobiology of SRS has been proven to be exceptionally effective. Traditionally, accepted

radiobiology has relied on the linear quadratic model (LQ) which evaluates effectiveness of

radiation delivery treatments by comparing daily doses. However, the concern of the potency and

toxicity of high-dose ablative radiosurgery has caused some physicians hesitation about whether

or not to adopt the beneficial and highly efficacious treatment method.17 Park, Papiz, Zhang, et

al17 explain an alternative method of analyzing the effects of stereotactic radiotherapy. This

study aimed to offer an alternative method of evaluating SRS treatments with a universal

survival curve (USC).17 The USC offers superior approximation of survival curves without

losing the strengths of the LQ model.17 The study looked at two classic radiobiological models:

the LQ and the multitarget.17 They tested the validity of the USC with previously published

parameters of both models for non-small-cell lung cancers.17 The results found that the USC can

26

be used to compare dose fractionation schemes to provide a well-justified rationale for ablative

doses.17

Another principal component to consider when planning and evaluating SRS is proper

calculation of the dose distribution. Ong, Cuijpers, Senan, et al20 investigated the impact of

calculation resolution using anisotropic analytical algorithms (AAA). They were looking

specifically at 3D-CRT utilizing small fields in homogeneous and heterogeneous mediums and

with the use of RapidArc plans.20 They evaluated the accuracy of the algorithms calculated using

grid sizes of 2.5 and 1.0 mm.20 It was found that 1.0 mm was superior to 2.5 mm and was

recommended.20 However, when using the smaller dose grid at 1.0 mm, the calculation times

were longer.20

Yet another crucial component to safe and effective SRS treatment delivery is imaging.

In the absence of quality imaging techniques, all of the above mentioned parameters become

obsolete. Ackerly, Lancaster, Geso, et al38 assessed the accuracy of the BrainLab ExacTrac

system for frameless intracranial stereotactic treatments. Couch parameters and image fusion

results were recorded for 109 SRS and 166 SRT cases and studied.38 1.25 mm slices were

obtained during the treatment planning CT.38 Slice thickness has been reported to impact the

accuracy of localization to bony anatomy, therefore, smaller slices were obtained.38 For SRS, the

uncertainty factors of ExacTrac calibration, image fusion, and intrafraction motion was 0.323-

0.393 mm in the longitudinal axis, 0.337-0.409 mm in the lateral axis, and 1.231-0.281 mm in

the anterior-posterior coordinates.38 The special accuracy was determined by using the principle

of invariance with respect to patient orientation and found to be 1.35 mm for SRS.38 In

conclusion, the study determined that the ExacTrac system was accurate and reliable for use in

SRS clinical practices.38

27

Chapter III: Methodology

Patients diagnosed with primary brain tumors or brain metastases may be candidates for

radiation therapy. Traditionally, 3DCRT or WBRT has been used as the treatment technique for

these lesions. However, SRS has been rapidly growing in popularity and can be applied to a

number of various benign and malignant intracranial lesions. SRS delivered via DCAT or

VMAT has the ability to increase local control and survival rates. Prior research has proven the

efficacy of SRS in conjunction with WBRT for brain metastases.7 The purpose of this study is to

compare treatment techniques for the delivery of SRS for intracranial tumors by looking at a

variety of dosimetric parameters.

Subject Selection and Description

For this retrospective research study, five to ten patients were selected using a purposive

sampling method; therefore, the study will involve a deliberate selection of individuals. By

using this method of sampling, it will be ensured that the patients included in the study meet

specific, pre-determined criteria. The patients selected will have intracranial tumors and meet

requirements for SRS treatment. The patients included in this research study will meet the

requirements of RTOG 95-08, which allowed a maximum tumor diameter of 4.0 cm. The plan is

for all patients included to have received treatment for brain metastases; however, this may

change to include patients treated for primary brain tumors. The patients included will have a

single lesion or multiple lesions. This has not yet been decided. The patients were all treated at

Gundersen Lutheran Health System in La Crosse, Wisconsin.

Instrumentation

A variety of different equipment is needed for this research study. A treatment planning

computed tomography (TPCT) scan will be obtained using a GE lightspeed R16. The precision

of SRS requires the patients to have extensive immobilization. The patients in the study may

have a halo placed. However, more than likely a reinforced Orfit facemask will be used, in

addition to an “S” frame. This frame extends over the edge of the treatment couch allowing for

increased couch angles, as well as less attenuation, during treatment delivery. Image fusion of

MRI and the TPCT will be required in order for the physician to accurately delineate the tumor

volume, as well as critical structures in proximity to the tumor volume. The treatment plans

developed for the patient’s in this study will use the Eclipse TPS (v10, Varian Medical Systems).

28

Two treatment plans will be created; one using VMAT RapidArc, in addition to another plan

using DCAT. The plans will be developed following RTOG 95-08 guidelines. Per the protocol,

total dose is dependent on the size of the lesion.19 An assigned total dose of 24 Gy will be

prescribed for planning a maximum tumor diameter of ≤ 2 cm, 18 Gy will be prescribed for a

maximum tumor diameter of 2.1-3.0 cm, and 12 Gy will be prescribed for a maximum tumor

diameter of 3.1-4.0 cm.19 The MLC dimensions will vary for each treatment technique.

RapidArc will utilize two full optimized, coplanar arcs around the patient with 120-leaf

millennium MLC (Varian Medical Systems), which project 5 mm width from isocenter in each

direction for the inner 10 cm. In contrast, DCAT will use seven non-coplanar arcs with micro

(m3) MLC (BrainLAB) that project 3 mm out to 2.1 cm on either side of isocenter , 4 mm for 3.3

cm on either side of isocenter and 5 mm out to 4.5 cm on either side of isocenter. For the above

DCAT technique, a standard table arrangement will be used setting the table approximately 27

degrees apart for each non-coplanar arc delivered. (90*, 63*, 36*, 10*, 350*, 323* and 296*).

The treatment planning calculations will be done using AAA due to its ability to accurately

calculate heterogenous mediums. For field sizes of < 3x3 cm2, a recent publication indicated the

significant improvement of dose calculation accuracy using AAA v10 when the calculation grid

size was reduced from 2.5 mm to 1.0 mm.20 Therefore, for this study we will set the calculation

grid size to 1.5 mm or less.

Data Collection

Data collection for this research study will consist of multiple steps. The five to ten

patients that will be chosen for this retrospective study have previously been treated for SRS;

therefore, MRI/TPCT fusion has already been completed. PTV volumes and critical structures

were previously contoured by the physician. Upon review of the previous planning, some

modification may be made in order to standardize the planning criteria of the patient population

included.

The next step in the process will be to re-plan utilizing the Eclipse TPS. Each patient will

have two plans developed, one using DCAT and the other using VMAT or RapidArc. The plan

is to create seven non-coplanar arcs with various table angles for DCAT and two full coplanar

arcs for VMAT. DCAT uses forward planning methods versus VMAT using inverse planning

optimization. Once these plans are completed, the next step will be to gather dosimetric

parameters including target coverage, conformity index, homogeneity index, gradient index,

29

integral brain dose and possibly a volume of the normal brain tissue receiving a certain dose,

which is yet to be determined.

Data Analysis

Data collection will be analyzed utilizing descriptive analysis. This type of analysis will

allow the large amount of data generated from the treatment plans to condense into

comprehensible and interpretable form. A dose volume histogram (DVH) will be utilized to

determine target coverage. Additionally, the mean, range and standard deviation will be

calculated. To determine isodose volumes, which is required to calculate the conformity and

homogeneity indexes, the “convert isodose level to structure” tool will be used. In order to

evaluate conformity index, the formula created by RTOG and Paddick21 will be utilized, PITV =

VRI/TV and CIPaddick = TV2RI/TVxVRI, respectively. PITV is defined as the RTOG conformity

index where VRI is the reference isodose volume and TV is the target volume. TVRI is the target

volume covered by the reference isodose.22 Two conformity indexes will be calculated because

the RTOG index does not penalize for the prescription isodose line that does not cover the target.

For evaluation of homogeneity index, HI = Dmax/VRI, where Dmax is the maximum dose to the

target will be used.22 The gradient index will be evaluated as well using a formula created by

Paddick23; GI = V50%RI/VRI, where V50%RI is defined as the volume of 50% of the reference

isodose. Calculation methods for integral brain dose and a volume of the normal brain tissue

receiving a certain dose is yet to be determined.

Limitations

A limitation to this study is that it pertains only to brain tumors treated with stereotactic

radiation, and thus similar planning evaluation index may not apply to other tumor sites such as

lung or abdominal masses. The study will be conducted using 6 MV beams for all treatment

plans. This can be considered a limitation since 15 MV will not be used and could possibly

provide a more conformal plan. Optimization parameters may be a limitation if the same

optimization objectives for each case are used. To date, most of the treatment planning

algorithms for SRS are still pencil-beam calculations (PBC) that do a very poor job for

heterogeneous medium, such as brain tissue. Therefore, it is a limitation that the study utilizes

AAA algorithm, as other algorithms will produce slightly different results.

30

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