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
2
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.
Graduate Program Director
_________________
Date
3
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 ...................................................................Error! Bookmark not defined.
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
6
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
7
the 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
8
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 wellcollimated 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 noninvasive 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
9
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 conebased, 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
10
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
15
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
16
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
17
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
18
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.
19
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
20
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
21
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 (noncoplanar)/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
22
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
23
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 dosevolume 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
24
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
25
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 microMLC 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 leafwidth 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
26
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
27
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 0.3230.393 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
28
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).
29
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,
30
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.
31
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