3D Image-guided Intracavitary Brachytherapy Treatment Planning for Cervical Cancer Using a Novel Shielded Applicator
Phase: NA
Conditions: Cervical Cancer
Sponsor: M.D. Anderson Cancer Center

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Protocol Page
3D Image-guided Intracavitary Brachytherapy Treatment Planning for Cervical 
Cancer using a Novel Shielded Applicator
2012-0546
Core Protocol Information
Short Title 
MRI Brachytherapy Applicator Study
Study Chair: 
Ann Klopp
Additional Contact:
Donna M. White
Toni Williams
Victoria Cox
Department:
Radiation Oncology
Phone:
713-563-6930
Unit:
1202
Full Title: 
3D Image-guided Intracavitary Brachytherapy Treatment Planning for Cervical Cancer using a 
Novel Shielded Applicator
Protocol Type:
Standard Protocol
Protocol Phase:
N/A
Version Status:
Terminated 05/10/2018
Version:
09
Submitted by:
Donna M. White--5/5/2014 11:07:49 AM
OPR Action:
Accepted by:  Virginia M Gonzales -- 5/13/2014 10:47:13 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

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Protocol Body
1.0 Objectives
Primary objective
Determine whether 3D Image-guided treatment planning can improve the quality of 

intracavitary brachytherapy in cervical cancer.
Secondary objectives
1. Determine if MRI imaging is superior to CT imaging in delineating a high risk target 
volume. 
2. Identify clinical and tumor characteristics of patients in whom CT or MRI can 
improve dosimetric tumor coverage and normal tissue sparing.
3. Evaluate the feasibility of MRI-based treatment planning utilizing the shielded MD 
Anderson adaptive applicator.
4. Compare resource utilization for MRI and CT based treatment planning as 
compared to standard film based planning techniques. 
2.0 Background
Role of Intracavitary Brachytherapy in Treatment of Cervical Cancer 
Intracavitary brachytherapy (ICBT) is a critical component of definitive radiation therapy 
for cervical cancer.  ICBT is typically administered upon completion of five weeks of 
external beam radiation therapy (EBRT).  Because of rapid dose fall-off, optimal implant 
placement allows for high dose delivery to the cervix and parametrial tissue while 
limiting dose to critical adjacent tissues, including the bladder, rectum and sigmoid 
colon.  Patients with small tumors have high central control rates and relatively low 
complication rates with this approach.  However, women with a larger volume of 
disease have higher rates of local recurrence.
1,2
Standard Intracavitary Brachytherapy
At MD Anderson, our standard and extensively validated approach has been to optimize 
implant geometry by careful implant placement and selection of the optimal applicator 
based on patient anatomy and disease extent.
3  Orthogonal x-ray films are used 
intra-operatively to verify optimal placement of the applicator and proximity to the cervix. 
Treatment planning is performed by optimizing dwell times for radiation sources which 
step through a series of dwell positions in the intrauterine tandem and vaginal 
applicator. Treatment decisions are informed by physical examination, evaluation of 
pre-treatment imaging and the type and position of the brachytherapy applicator used 
and for specific patients additional 3D imaging obtained at the time of implant.  The goal 
is to create a dose distribution which delivers adequate dose to sterilize disease in the 
tumor bed and parametrial tissues while minimizing dose to bladder, rectum and 
sigmoid colon.  The dose to bladder and rectum is limited to standard constraints (65-70 

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Gy to the rectum and 70-75 Gy to the bladder) which are represented by standard 
reference points on orthogonal images. For patients with particularly challenging 
anatomy or implants, additional imaging (in the form of CT or MRI) is often obtained 
following the implant to verify placement of the system.
Image Guided Brachytherapy
The acquisition of 3D imaging at the time of brachytherapy allows for volumetric 
evaluation of dose to the target (the residual tumor and the whole cervix) as well as 
adjacent normal tissues. CT images taken with the intracavitary applicator in place are 
increasingly being used for brachytherapy treatment planning. Recently, a number of 
investigators have advocated the use of MRI-based treatment planning. Following 
acquisition, images can be exported to the radiation treatment planning system where 
dose to the target and normal tissues can be calculated (Figure 1).  Dwell times for the 
iridium stepping source within the applicator can then be adjusted in order to modify the 
dose based on individual patient and tumor anatomy and response to prior treatment 
thus optimizing tumor coverage and minimizing dose to organs at risk.
CT- and MRI-based planning have advantages and disadvantages.  CT imaging 
provides excellent visualization of normal pelvic tissues, but the tumor is generally 
difficult to distinguish from normal cervix as a result of their similar electron density.  
While still more expensive than 2D imaging, CT imaging is readily available to most 
radiation oncologists, and is the most common form of image-based treatment planning 
being used in the US today.
4 
T2 MRI images provide better visualization of tumor and paracervical soft tissue 
extension than CT.
5-7 This may be important, because areas of tumor extending into 
adjacent tissues may receive an inadequate dose with standard brachytherapy 
treatments.  
Figure 1.  Sagittal T2 weighted MRI with dose distribution displayed.  HR-CTV located 
centrally in aqua color, bladder in yellow, foley bulb in green, and rectum located 
posteriorly in aqua delineated with red arrows. 

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Within the last decade there has been a European lead movement towards MRI-based 
treatment planning in which the brachytherapy dose is prescribed to a 3D image-derived 
target volume with set constraints set for doses to critical organs at risk for radiation 
injury. The GEC-ESTRO working group developed recommendations for concepts and 
terms in 3D image-based treatment planning and has worked to define targets 
compatible with clinical experience from three prominent European institutions.
8,9 Early 
clinical results using the above described systematic approach have been viewed as 
promising with 3-year local control rates of 82% for patients with tumors >5 cm and 96% 
for 2-5 cm.
10 However, these local control rates are not obviously different from those 
reported for patients treated at MD Anderson using traditional techniques.
1,11
Interestingly, the practice of obtaining 3D imaging with the applicator in place has been 
rapidly adapted across the United States with a 2010 American Brachytherapy Society 
(ABS) patterns of care study showing that the majority of physicians obtain CT or MRI 
after insertion of the intracavitary device.
4  Despite the fact that MRI is the primary 
imaging modality used in the studies supporting 3D image guided brachytherapy the 
ABS patterns of care study shows that 70% of respondents use CT imaging while only 
2% use MRI. 

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It is important to clarify the magnitude of potential benefit from these new approaches 
because utilization of 3D image-based treatment planning is substantially more 
expensive than standard planning; one study reported increased costs of 10-15% to 
setup 3D image based gynecologic brachytherapy.
10  MRI in particular, despite its 
potential benefits, is expensive, logistically difficult and is not as widely available for 
radiation oncology treatment planning as CT imaging. It also requires the use of 
specially-designed MRI-compatible applicators.  As a result, Viswanathan and 
colleagues suggested a standardized approach to CT-based contouring.
12  When the 
authors compared CT with MRI, they found that CT was adequate for analysis of the 
doses to organs at risk, but that CT-based standardized contours tended to 
overestimate tumor width, leading to significant differences in target coverage.  While 
this study is the only published series comparing CT to MRI, it included only 10 patients 
with a single radiation oncologist responsible for the contouring.  Additionally, the CT 
quality was poor (with 4 mm slice thickness ) compared to current standards (typically 
1-2 mm slice thickness).   To date, there are no studies evaluating the role of modern 
CT scanning in an adequate number of patients to determine if there is a select group in 
which CT may be equivalent to MRI in delineating a target volume.
MRI-Compatible Adaptive Applicator
Because utilization of MRI for treatment planning requires special MRI-compatible 
applicators, the shields that are used to reduce dose to the bladder and rectum in 
standard applicators have been eliminated.  The use of shields in standard applicators 
have been shown to reduce the dose to the bladder and rectum by as much as 25%, 
but create extensive image artifacts hindering image based brachytherapy planning.
13,14 
At MD Anderson, we have developed a novel applicator with moveable MRI-compatible 
shields, which allows for acquisition of high resolution CT images.15  Our group recently 
completed a prospective pilot study using this applicator and demonstrated the 
feasibility of its use in ICBT planning with superior image quality when the adaptive 
shields were shifted from the treatment position as compared to in the treatment 
position.16  The applicator that we are using is based off  of Nucletron's FDA approved 
MRI compatibility applicators (see Appendix C).
3.0 Rationale
Standard approaches for ICBT in cervical cancer are backed by extensive clinical 
experience with high rates of local control and relatively low toxicity.
17  MRI- and 
CT-based treatment planning have potential to further improve outcomes for certain 
patients by allowing tailored treatment based on patient specific anatomy and tumor 
response. 
The current standard at our institution takes into consideration initial clinical exam, 
pre-treatment imaging, pre-brachytherapy examination under anesthesia, applicator 
features, quality of the brachytherapy placement and doses to normal tissue reference 

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points collectively allowing for development of the optimal 2D brachytherapy treatment 
plan. As part of this protocol each patient will have a 2D treatment plan created in this 
way prior to the treating physician reviewing the MRI or CT obtained with the applicator 
in place.  
Currently at our institution imaging, including CT and MRI, is taken into account on a 
case-by-case basis allowing for subtle adjustments to the treatment plan as necessary. 
This protocol will deliver treatment according to this standard practice while 
systematically evaluating the potential impact of image-based planning on the quality of 
treatment planning.   
Patients enrolled on this protocol will have both a CT and MRI obtained after insertion of 
the intracavitary applicator. Once the optimal 2D plan has been created, these images 
will be reviewed by the treating physician before treatment to rule out any possible rare 
major deviations in applicator placement such as uterine perforation as well as to inform 
the treating physician of size and location of any residual disease and proximity of 
organs at risk.  This will be done so that subtle adjustments to standard loadings can be 
made.   For example, if bowel is identified to be in close proximity to the implant the 
adjacent dwell positions may be loaded to a lesser degree in order to better spare that 
bowel. Patients will be treated with this 2D plan informed by the 3D images consistent 
with our current standard of care for patients who have additional imaging at the time of 
implant.  
Obtaining the CT and MRI will also allow us to create additional 3D image based 
treatment plans which will be used only for comparison purposes (not for actual 
treatment).  We will compare the 3D image based treatment plans to the standard 2D 
treatment plan to determine if we are able to dosimetrically improve target coverage, 
while respecting adjacent tissue tolerances, with either form of 3D image guidance.  We 
will also keep track of the number of person-hours required for planning using each 
imaging modality by documenting the time spent generating contours on both CT and 
MRI and the amount of time spent generating each individual plan.  We will also keep 
track of the amount of time that each additional imaging modality takes to acquire. 
Through the billing department, we will also capture the fees associated with the 
additional MRI and CT scan as well as the charge of the MRI compatible applicators for 
each patient and compare this to the fees for a routine implant in which a comparable 
standard applicator is used and MRI and CT at the time of implant are not obtained.  In 
combination, this will allow us to determine which imaging modalities are most efficient 
and practical and which add the most to the treatment planning process.  Additionally, 
we will determine if there are specific patient and tumor characteristics most and least 
likely to gain from image guided brachytherapy.
4.0 Patient Eligibility
Inclusion Criteria

Women with stage > IB2 cervical cancer treated with definitive chemoradiation or 
radiation therapy who require intracavitary brachytherapy.

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Exclusion criteria

Patient or tumor anatomy that requires use of a non-MRI-compatible applicator.

Patients who require interstitial brachytherapy.

Patients whose treating physician feels that they require additional 3D imaging at 
the time of implant based on physical exam or initial findings

Patients with implantable cardioverter-defibrillator, pacemaker or other implanted 
device, which precludes MRI acquisition. 
5.0 Treatment Plan
Patient Evaluation and External Beam Therapy
Patients may not be enrolled on protocol until after external beam therapy has been 
started so pretreatment workup will be according to standard practice which typically 
includes CBC, BUN/Cr, chest imaging, CT abdomen/pelvis, MRI of the pelvis, and 
physical examination.  Patients who are candidates for this protocol will have physical 
exam findings documented at the time of diagnosis and on the day of the implant.  
Pertinent information including whether tumor is exophytic or bulky/endocervical, tumor 
diameter, parametrial involvement, pelvic sidewall, rectal, or vaginal involvement will be 
documented on a protocol specific form (Form A, Appendix D).  Patients will then be 
treated with external beam radiation therapy with or without chemotherapy as 
determined by the treating radiation oncologist and gynecologic oncologist.  External 
beam irradiation may consist of conventional treatment or Intensity Modulated Radiation 
Therapy (IMRT). 
Intracavitary Applicator Placement
On the day of the implant, an examination under anesthesia will take place per our 
standard approach.  The tumor characteristics will be documented on Form A (Appendix 
D).  The appropriate MRI-compatible applicator will be inserted using ultrasound 
guidance to verify tandem placement in the uterus.  Tandem and ovoids, tandem and 
cylinders, or tandem and ring will be chosen to accommodate the patient’s tumor and 
vaginal anatomy. Gel impregnated gauze packing will be placed in the vagina for 
stabilization of the applicator and displacement of rectum and bladder.
Per our standard treatment protocol, orthogonal plain films will be obtained in the 
operating room to assess appropriate applicator placement.  Optimized loadings will 
then be recommended according to standard rules. Following the reversal of 
anesthesia, patients will be taken to recovery.  After recovery from anesthesia, patients 
will be transported to diagnostic imaging for MRI acquisition and to the department of 
radiation oncology for CT imaging.

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MRI Acquisition
Currently, baseline MRIs are obtained on the majority of patients at diagnosis and this 
will be performed according to standard practice. 
On the day of the intracavitary implant, after placement of the MRI compatible 
applicator, MRI acquisition will be performed on 1.5 T or 3 T scanner. Images will be 
obtained utilizing an 8 channel cardiac coil.  MRI compatibility of the applicator will be 
documented prior to placement of the patient in the scanner. High resolution T2 FRFSE 
images will be obtained in the coronal plane (3mm contiguous slices/FOV 18-22 
cm/TR>3000/TE>100msecs). The coronal plane will be used to generate oblique 
sagittal and oblique axial images of the cervix and applicator – parallel and 
perpendicular to the applicator device within the cervix, respectively. Axial T2 weighted 
T2 FRFSE images of the entire pelvis will be obtained at the end of the exam.  
Additionally a T2 Axial Cube image with isotropic 1mm voxels will also be obtained.  On 
the day of the implant, MRI images will be evaluated for adequate applicator position 
within the uterus and cervix to rule out any possible rare major deviations in applicator 
placement such as uterine perforation. 
CT Acquisition
The same procedure used in previously approved protocol 2008-0455 will be used for 
CT acquisition. In brief, CT images will be acquired using the GE Lightspeed CT 
simulators available in the MDACC Radiation Oncology clinic.  Images will be acquired 
with 120 keV, 200mA with 2 mm slice thickness. Patients with shielded applicators will 
have the shields shifted during image acquisition, according to previous protocol 
specifications. After acquisition of the CT, the medical physicist will insure that both 
rectal and bladder shields are locked into the radiation treatment position and check the 
overall applicator integrity. A CT scout image will also be acquired to verify that the 
shields have been moved to the appropriate place.  A medical physicist will be present 
during the CT acquisition for patients with adaptive applicator which requires shield 
shifting to insure correct procedure is followed. It is expected that patients will spend 
15-30 minutes in the Radiation Oncology department for the CT procedure.
Contouring and Treatment Planning
As is standard, our dosimetrists will develop a 2D plan according to the loadings 
recommended by the physician based on the physical examination, initial diagnostic 
imaging ,and orthogonal films.  As is routine the treating physician will then evaluate the 
2D plan looking at doses to specific points (rectal and bladder) delineated on the 2D 
imaging and make adjustments as they see fit.  Following acquisition of both MRI and 
CT and finalizing of the 2D treatment plan, images will be reviewed by the treating 
physician before treatment to rule out any possible rare major deviations in applicator 
placement such as uterine perforation.  The 3D imaging will also be used to inform the 
physician prescribing the dose of the location and size of any residual disease and 

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location of critical organs such that they may make subtle adjustments to the 2D 
treatment plan.  Based on this a new plan, 2D plan informed by 3D imaging, will be 
created, and the patient will be treated with this plan. 
Dosimetric Contouring Study
As part of the lab based portion of this protocol, the MRI and CT images will be 
uploaded into our brachytherapy treatment planning software, Oncentra.  After 
reviewing the patient’s initial diagnostic imaging and physical examination at the time of 
diagnosis and the time of implant the radiation oncologist involved in the procedure and 
one additional radiation oncologist will contour a HR-CTV based on the GEC-ESTRO 
guidelines (Appendix E) on the CT followed by the MRI. One of the primary 
investigators will also contour a HR-CTV as well as critical structures (rectum, bladder, 
sigmoid colon) on both the MRI and CT scan. The 2D plan will then be registered on the 
MRI and CT within the treatment planning software.  Based on the primary investigators 
approved contours several additional plans will be created for purpose of comparison 
(See Table 1).
The contours devised by all three physicians on MRI and CT will also be compared to 
determine the interobserver variability for each specific imaging modality.  Contours will 
be imported into Computerized Environment for Radiation Research (CERR), an 
open-source MATLAB (TheMathWorks, natick, MA) - based radiation therapy planning 
analysis tool. The "apparant agreement" method will be used to calculate the apparant 
volume overlap such that a volume - agreement cumulative histogram can be 
generated.
 Dosimetric Treatment Planning Study
The first plan will be a CT based plan and will be optimized to improve the HR-CTV D90 
(dose received by 90% of the target volume) to as close to 85 Gy as possible without 
exceeding the known tolerance dose to rectum and bladder (D2cc of rectum < 70 Gy 
and  D2cc of bladder < 90 Gy).18  The second plan will be optimized the same as the 
first but with the HR-CTV, rectum, and bladder delineated on MRI instead of CT.  
Table 1
Plan
Description
1) 2D Plan
This will be based on the standard loadings 
recommended by the physician after 
performing physical exam at time of implant 
and review of orthogonal films delineating 
applicator placement. The initial diagnostic 
imaging will be reviewed and help to inform 
this plan and adjustments will be made 
based on point doses. 
2) 2D Plan informed by 3D images at time This will be based on the standard loadings 

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of implant.
recommended by the physician after 
performing physical exam at time of implant 
and review of orthogonal films delineating 
applicator placement. The initial diagnostic 
imaging as well as the MRI and CT scan at 
the time of implant will be reviewed and help 
to inform this plan. The patient will be treated 
with this plan according to standard practice.
3) ICBT CT based optimized plan
This plan will start with the above described 
2D plan and will be optimized to target the 
CT based HR-CTV (also informed by initial 
diagnostic imaging) with the same objectives 
as the GEC-ESTRO MRI guidelines. 
4) GEC-ESTRO MRI based optimized plan This plan will start with the above described 
2D plan and will be optimized according to 
GEC-ESTRO guidelines taking into account 
the patient’s initial diagnostic imaging as well 
as MRI scan with the applicator in place.
Each of the three treatment plans will be registered on the MRI, and the MRI contours 
will be used as the gold standard such that each treatment plan will be evaluated for its 
coverage of the HR-CTV and ability to meet constraints for the adjacent organs at risk.  
For each of the three treatment plans, we will evaluate the D90, D100, V100, V150, 
V200, for the HR-CTV and IR-CTV as well as the D0.1, 1, 2 cc for bladder, sigmoid, and 
rectum (see Table 2). Conformality index (CI=V100%/VCTV) and dose homogeneity 
index (DHI= (V100%-V150%)/V100%) will be calculated for HR-CTV. 
Table 2 Using the contours created on MRI (HR-CTV, IR-CTV, Rectum, Bladder, 
Sigmoid) the following parameters will be evaluated for each of the three treatment 
plans.

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6.0 Statistical Considerations and Analysis
Primary Endpoint
The goal of this study is to determine if 3D image guided treatment planning allows for 
improved tumor coverage while respecting normal tissue constraints as compared to 
standard 2D treatment planning.  To address this, the D90 (or the dose to 90% of the 
HR-CTV volume) and maximally irradiated 2 cc of the bladder (D2 cc bladder) and 
rectum (D2 cc rectum) will be compared (these parameters have been reported in the 
past to correlate with toxicity). 
To better understand the dose distribution the other parameters listed in Table 2 will 
also be documented and compared for each of the three plans described above. 
Sample Size
Preliminary data were collected on 4 patients who received MRI with the brachytherapy 
applicator in place.  After the patient was treated a GEC-ESTRO MRI based manually 
optimized plan was created and compared to the 2D plan. Data for HR-CTV D90 and 
maximally irradiated 2 cc of bladder and rectum were collected.  The paired differences 
in the 3 parameters of interest were:

HR-CTV D90 - mean difference of 459.91 cGy with a standard deviation of 303.69 
cGy. The mean HR-CTV 90 for the standard film method was 1368.73 cGy.

D2 cc bladder – mean difference of 407.11 cGy with a standard deviation of 250.81 
cGy. The mean D2 cc bladder for the standard film method was 1474.44 cGy.

D2 cc rectum – mean difference of 159.83 cGy with a standard deviation of 194.44 
cGy. The mean D2 cc rectum for the standard film method was 962.50 cGy. 
We would like to demonstrate an improvement (i.e., increase) in HR-CTV D90 of at 
least 20% (i.e., at least 273.75 cGy) with MRI based planning over standard 2D 
planning. With a sample size of 30 patients we will have 96% power with a 2-sided 
significance level of 0.0056 to detect an improvement of at least 20% in the HR-CTV 
D90 with the MRI guided procedure using a t-test.
With a sample size of 30 patients we will have 90% power to detect an increase in D2 
cc bladder of 0.80 standard deviations, or 200 cGy (i.e., 14.4%) with a 2-sided 
significance level of 0.0056 using a t-test.
With a sample size of 30 patients we will have 90% power to detect an increase in D2 
cc rectum of 0.80 standard deviations, or 155 cGy (i.e., 16.1%) with a 2-sided 
significance level of 0.0056 using a t-test.
We use the Bonferroni correction to the significance level since we are testing 3 
methods × 3 dosimetry parameters = 9 hypotheses (e.g., 0.05/9 = 0.0056). These 
sample size calculations were performed using nQuery Advisor ® 7.0 (Copyright © 

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1995-2007, Statistical Solutions, Saugus, MA). 
We anticipate that 25% of patients will not be evaluable due to inability to accommodate 
an MRI compatible applicator.  In addition, we anticipate that 30% of patients will 
receive tandem and cylinders or non-adaptive tandem and ovoids. The applicator type 
used significantly alters the dose distribution which is expected to impact the relative 
dosimetric benefit of MRI. As a result, the primary analysis will be limited to patients with 
the adaptive, shielded ovoid, which is the most commonly used applicator in 
non-protocol patients.  We would therefore like to accrue a total of 57 patients in order 
to achieve our goal of 30 evaluable patients treated with the adaptive tandem and ovoid 
system. 
Analysis
We will use summary statistics to describe the clinical and demographic characteristics 
of patients. We will similarly summarize the dosimetry parameters listed in Table 1 for 
each of the three planning methods noted above. 
We will compare the HR-CTV D90, D2 cc bladder, and D2 cc rectum for the MRI based 
treatment plan (method #4) and CT based treatment plan (method #3) to the standard 
2D plan (method #1) and the 2D plan informed by 3D imaging (method #2).  We will use 
analysis of variance methods with Dunnett’s procedure to compare the outcomes from 
each of planning methods with the outcomes from planning method #1. We will similarly 
compare the other dosimetry parameters between the various planning methods.
We will also keep track of the number of person-hours required for planning using each 
imaging modality by documenting the time spent generating contours on both CT and 
MRI and the amount of time spent generating each individual plan.  Through the billing 
department, we will also capture the fees associated with the additional MRI and CT 
scan as well as the charge of the MRI compatible applicators for each patient and 
compare this to the fees for a routine implant in which a comparable standard applicator 
is used and MRI and CT at the time of implant are not obtained.
Secondary Endpoint
As mentioned above, we will also track of the number of person-hours required for 
planning using each imaging modality by documenting the time spent generating 
contours on both CT and MRI and the amount of time spent generating each individual 
treatment plan.  We will also keep track of the amount of time each additional imaging 
modality take to acquire. Through the billing department, we will capture the fees 
associated with the additional MRI and CT scan as well as the charge of the MRI 
compatible applicators for each patient and compare this to the fees for a routine 
implant in which a comparable standard applicator is used and MRI and CT at the time 
of implant are not obtained.  For the purpose of comparison each of these data points 
will be compared to each other and to 2D orthogonal plans using. 

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7.0 References
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