Clinical Impact of a Volumetric Image Method for Confirming Tumor Coverage With Ablation on Patients With Malignant Liver Lesions (COVER-ALL)
Phase: PHASE2
Conditions: Malignant Liver Neoplasm
Sponsor: M.D. Anderson Cancer Center

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Clinical impact of a volumetric image method for confirming tumor coverage with 
Ablation on patients with malignant Liver Lesions  
(COVER-ALL) 
 
Principal Investigator:  Bruno C. Odisio MD 
Co-Investigators:  Kristy K. Brock, PhD, Jean-Nicolas Vauthey, MD, Sanjay Gupta, 
MD, Scott Kopetz, MD,  
Collaborators: HyunSeon Kang, MD, Veronica Cox, MD, Ahmed Kaseb, MD, Imad 
shureiqu, MD, Kanwal Raghav, MD, Michael Overman, MD, Joshua Kuban, MD, 
Kamran Ahrar, MD, Ching-Wei Tzeng, MD, Yun Shin Chun, MD, Bryan Fellman, 
Hop Tran Cao, MD, Milind Javle, MD, Van K Morris, MD, Timothy Newhook, MD, 
Zeyad Metwalli, MD, Ketan Yogesh Shah, MD, Milan Patel, MD 
Statistician:  Bryan Fellman 
Outside collaborator: Joe E Ensor PhD - Houston Methodist Cancer Center, 
Houston Methodist Research Institute, jeensor@houstonmethodist.org, 6670 
Bertner Ave, Houston, 77030 
 
 
 

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Clinical impact of a volumetric image method for confirming tumor coverage with Ablation on patients 
with malignant Liver Lesions ......................................................................................................................... 1 
(COVER-ALL) .................................................................................................................................................. 1 
Principal Investigator:  Bruno C. Odisio MD .................................................................................................. 1 
Co-Investigators:  Kristy K. Brock, PhD, Jean-Nicolas Vauthey, MD, Sanjay Gupta, MD, Scott Kopetz, MD, 1 
Collaborators: HyunSeon Kang, MD, Veronica Cox, MD, Ahmed Kaseb, MD, Imad shureiqu, MD, Kanwal 
Raghav, MD, Michael Overman, MD, Joshua Kuban, MD, Steven Y. Huang MD, Kamran Ahrar, MD, Ching-
Wei Tzeng, MD, Yun Shin Chun, MD, Bryan Fellman, Hop Tran Cao, MD, Milind Javle, MD, Van K Morris, 
MD, Timothy Newhook, MD, Zeyad Metwalli, MD, Ketan Yogesh Shah, MD .............................................. 1 
Statistician:  Bryan Fellman ........................................................................................................................... 1 
Outside collaborator: Joe E Ensor PhD - Houston Methodist Cancer Center, Houston Methodist Research 
Institute, jeensor@houstonmethodist.org, 6670 Bertner Ave, Houston, 77030 ......................................... 1 
List of Abbreviations ..................................................................................................................................... 3 
OBJECTIVES ................................................................................................................................................... 4 
1.1 
Primary Objective .......................................................................................................................... 4 
1.2 
Secondary Objectives .................................................................................................................... 4 
BACKGROUND ............................................................................................................................................... 4 
1.3 
Rationale ....................................................................................................................................... 4 
1.4 
Clinical Impact ............................................................................................................................... 6 
1.5 
Mechanism .................................................................................................................................... 9 
ELIGIBILITY ................................................................................................................................................... 12 
1.6 
Inclusion Criteria ......................................................................................................................... 12 
1.7 
Exclusion Criteria ......................................................................................................................... 13 
NUMBER OF PARTICIPANTS ........................................................................................................................ 13 
1.8 
Method ....................................................................................................................................... 14 
1.9 
Collecting Time Points ................................................................................................................. 20 
PROCEDURE TO OBTAIN CONSENT ............................................................................................................. 20 
PATIENT INFORMATION AND CONFIDENTIALITY PLAN .............................................................................. 20 
STATISTICAL CONSIDERATIONS ................................................................................................................... 21 
PROTOCOL MONITORING PLAN .................................................................................................................. 24 
DATA COLLECTION PLAN ............................................................................................................................. 25 

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REFERENCES ................................................................................................................................................ 27 
QUESTIONNAIRES ....................................................................................................................................... 30 
QUALITY OF LIFE QUESTTIONAIRE .............................................................................................................. 32 
 
 
List of Abbreviations 
ASA: American society of anesthesiologists 
CECT: contrast-enhanced computed tomography 
CLM: colorectal liver metastasis 
CT: computed tomography 
DIR: deformable imaging registration 
DTA: distance to agreement 
ECOG: eastern cooperative oncology group classification 
FEA: finite element analysis 
INR: international normalized ratio 
LTP: local tumor progression 
LTPF: local tumor progression-free survival 
MAM: minimal ablation margins 
MR: magnetic resonance 
MW: microwave ablation 
OS: overall survival 
PTA: percutaneous ablation 
QOL: quality of life 
RFA: radiofrequency ablation 
TRE: target registration error 

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OBJECTIVES 
1.1 Primary Objective 
 
To evaluate if the intra-procedure feedback of a biomechanical deformable 
registration volumetric image method during percutaneous ablation will increase the 
minimal ablation margins on a three-dimensional computed tomography-generated 
analysis. 
1.2 Secondary Objectives 
 
1. To assess whether applying the proposed method during percutaneous ablation 
improves local tumor progression-free survival (LTPFS) rates; 
2. Evaluate impact of software use on procedure workflow; 
3. Impact of software use on complication rates, quality of life, liver function; 
4. Evaluate oncological outcomes (intra-hepatic and overall progression-free survivals, 
and overall survival)  
BACKGROUND  
1.3 Rationale  
 
Primary liver cancer is the second leading cause of death worldwide with an 
estimated 788.000 related-deaths in 2015. The global burden of primary liver cancer can 
also be demonstrated by the impact on disability-adjusted life-years, which was estimated 

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in 20.578.000 in 2015. In addition to primary liver cancer, approximately two-thirds of all 
the 774.000 colorectal cancer-related deaths - the third most common cause of cancer-
related death worldwide and the most common cause of metastatic liver cancer - are 
attributed to the presence of colorectal liver metastasis (CLM). Collectively, primary and 
secondary liver cancers are responsible for over 1 million deaths per year worldwide. 
Moreover, it is expected an increase on the incidence on both primary and secondary 
liver cancers in the next decades owing to population growth and aging. Therefore, 
effective therapies for the treatment of primary and secondary liver cancers are needed. 
Among the curative treatments available for primary liver cancer, surgical resection 
(or liver transplantation) and ablation are both considered the standard of care on patients 
with very early and early stage accordingly to the Barcelona Clinic Liver Cancer staging 
and treatment strategy (1). Contrarily, for secondary liver cancers such as colorectal 
cancer liver metastasis, surgical resection is still considered the modality of choice. 
Unfortunately, only 20% of the patients with colorectal liver metastasis are considered 
surgical candidates (2), with percutaneous thermal ablation used as an acceptable 
alternative for the remaining of the non-surgical candidates (3), highlighting the 
importance of this therapy as a therapeutic option. Moreover, results of prospective phase 
II randomized clinical trial demonstrated improved overall survival rates among patients 
treated with a combination of percutaneous liver ablation and systemic chemotherapy for 
CLM when compared to patients treated with systemic chemotherapy alone (4). 
Currently, several ablation modalities are available for clinical use. Among those, 
radiofrequency ablation (RFA) and microwave (MW) coagulation are the most commonly 

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utilized. Such modalities have fundamental differences in the way tumor destruction is 
obtained. RFA promotes tumor destruction by the delivery of an alternating electrical 
current within the tumor resulting in frictional heat and movement of electrons within the 
lesion and surrounding tissues, whereas MW promotes tissue heating by causing polar 
water molecules to continuously realign with an oscillating electromagnetical field that 
emanates from the microwave antenna. Both technologies produces tissue friction and 
heat induces cellular destruction via coagulative necrosis. More recently, MW has been 
used more frequently in clinical practice given its advantages in achieving higher ablation 
temperatures and larger ablation zones. Nevertheless, when compared to RFA, MW is 
associated with a lower level of predictability between the desired ablation zone planned 
and the actual ablation zone achieved. Such discrepancy might affect both the safety of 
the procedure (i.e. larger unanticipated ablation zones with damage of critical structures 
adjacent to the ablated tumors) as well the oncological outcome of it (i.e. smaller ablation 
zone not encompassing the entire tumor volume). Moreover, tissue volumetric loss are 
more prominent with MW coagulation when compared to RFA, which limits the ability of 
the operator to ascertain with confidence adequate tumor coverage. Therefore, tailored 
high-precision image-guidance during ablation is critical for reducing procedure-
associated complications and achieve optimal outcomes. 
1.4 Clinical Impact 
 
Among the local therapies utilized for liver cancers, percutaneous thermal ablation 
has become a widely utilized option for patients not eligible for surgery, with most recent 
series demonstrating similar 5-year overall survival rates between surgery and ablation 

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(5-7). This highlights the efficacy of this treatment modality on prolonging OS in patients 
with liver cancers (4). 
In order to achieve optimal results with ablation, low rates of local recurrence (also 
known as local tumor progression [LTP]) at the treated tumors should be obtained. More 
recently, results of a prospective randomized phase II trial demonstrated that patients 
with CLM treated liver ablation in association with systemic chemotherapy had 
significantly longer overall survival rates (OS) when compared to patients treated only 
with systemic chemotherapy (4), emphasizing the role of aggressive local treatment on 
prolonging OS in patients with unresectable CLM. In an effort to improve local disease 
control and oncologic outcomes after liver ablation, several factors have been studied 
(15-19). Among the known factors associated with improved local tumor control with 
ablation, lesion diameter < 3 cm, number and location of tumors, and minimal ablation 
margins achieved around the target tumor(s) are widely recognized as critical variables, 
with the latter being the only one passive for modification during treatment delivery. 
Moreover, it has been recently described that biological factors such as the RAS 
mutational status are also prognostic indicators for local recurrence and survival in 
patients undergoing ablation of CLM and have prompted recommendations for wider 
ablation margins in patients with RAS-mutated tumors (8, 20), suggesting that the 
minimal ablation margin acceptable for optimal disease control needs to be tailored to 
distinct tumor subtypes. 
In order to provide adequate ablation margins, several elements are important: 
firstly, it is critical to have optimal definition of the tumor extent on intra-procedural CT 

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image; secondly, confirmation of precise probe placement in relation to the tumor is 
needed intra-procedurally; thirdly, the volumetric loss and peri-tumoral tissue 
inflammation promoted by the ablation limits the ability to evaluate with confidence the 
ablation margin intra-procedurally, therefore requiring a magnetic resonance (MR) or 
computed tomography (CT) study to be performed within 1-2 months following ablation 
procedure, a long period to evaluate the primary efficacy of this modality. Taking all 
together, those factors points to the need of having improved intra-procedurally imaging 
assessment of patients undergoing percutaneous ablation.  
Currently, there are no commercially available tools that provide a robust and 
accurate method for tumor mapping and ablation confirmation that takes in consideration 
the biomechanical conformational changes promoted by this therapy. We hypothesize 
that local tumor control following percutaneous ablation of liver cancers will be 
significantly improved with the application of a dedicated anatomical linear elastic 
biomechanical model for treatment guidance and efficacy assessment by enabling the 
operator to accurately identify the tumor for ablation probe placement and assess intra-
procedurally the minimal ablation margins, therefore increasing efficacy of percutaneous 
ablation therapy, ultimately improving liver progression-free survival rates. 
Our preliminary data shows that our biomechanical model can accurately map the 
tumor, defined on pre-treatment computed tomography (CT) imaging, onto an intra-
procedural CT image and is insensitive to imaging artifacts associated with ablation 
probe. We hypothesize that our innovative approach to modeling the tissue changes 
related to the ablation procedure will enable intra-procedure monitoring of the ablation 

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margin relative to the tumor. In addition, the combination of these technologies will 
provide further detailed information on the relationship between progression-free survival 
local tumor progression-free survival (LTPFS) and the ablation margins achieved.  
1.5 Mechanism 
 
A 
multi-organ 
finite element model 
(FEM)based 
deformable 
image 
registration 
(DIR) 
method (Morfeus) has 
been developed in a 
previously funded R01 and extensively validated on several sites including head and 
neck, lung, liver, stomach, esophagus, pancreas, prostate, rectum, cervix, and extremity 
sarcoma (8-29). A commercially available FEM pre and post processes (HyperMesh, 
Altair Engineering, Troy, MI) and a Finite Element Analysis (FEA) software package 
(ABAQUS, ABAQUS Inc, Pawtucket, RI) are utilized for model creation and analysis. 
Morfeus, is briefly described below, illustrated in Figure 1, and described in detail in the 
referenced publications: Briefly, manual contouring of regions of interest are generated 
and converted to a 2D surface mesh (clouds of nodes, connected to form elements). The 
number of elements can be reduced, leading to increase in efficiency, by combining 
elements and smoothing regions of high frequency.  
Figure 1. Morfeus schematic. Contours from reference volume (planning CT) and 
test volume (generated semi-automatically) are matched by Finite Element 
analysis 

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This surface mesh is a shell from which a 3D volume mesh is created, consisting of 
tetrahedral elements. Multi-organ models are created by constructing surface interfaces 
between neighboring region of interest meshes to govern their interaction. Boundary 
conditions, or loads applied to the FEM (e.g. force, moment, constraint, or pressure), 
provide a relationship between the initial and secondary representation of the mesh. 
Preliminary investigations focused on the use of applied constraints, or set 
displacements, assigned to a subset of elements in the model, determined by projecting 
the nodes on the surface of one region of interest onto a surface representation of the 
same region of interest constructed from another imaging session. Finite Element 
Analysis (FEA) determines the results of the boundary conditions for all nodes in the 
model. In summary, the method does not explicitly use intensity information in the 
registration, only for the manual delineation of regions of interest, the registration process 
is identical for images of the same or different modalities, the registration is driven by the 
alignment of a subset of the region of interest surfaces using a guided surface projection 
method, and the full deformation map (i.e. points in space with defined displacements), 
relating two images, is calculated using biomechanical models and solving the 
constitutive equations using FEA.  
This algorithm was licensed to RaySearch Laboratories (Stockholm, Sweden) for 
integration into their radiation therapy treatment planning system RayStation. The 
algorithm was extensively validated to confirm that the integration was performing with 
the same accuracy as the in-house developed system. Overall, the mean distance to 
agreement (DTA) was ≤ 1.0 mm for controlling structures (i.e. the liver) and 1.0–3.5 mm 

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for implicitly deformed structures (i.e. the kidneys) on average. Target registration error 
(TRE) ranged from 2.0 mm on prostate MR to 5.1 mm on lung MR on average, within 0.1 
mm or lower than the image voxel sizes. Accuracy was not overly sensitive to changes in 
the material properties or variability in structure segmentations, as changing these inputs 
affected DTA and TRE by ≤ 0.8 mm. Maximum DTA > 5 mm occurred for 88% of the 
structures evaluated although these were within the inherent segmentation uncertainty 
for 82% of structures. Differences in accuracy between the commercial and in-house 
research implementations were ≤ 0.5 mm for mean DTA and ≤ 0.7 mm for mean TRE.  
Deformable image registration for multi-modality imaging for treatment planning 
and guidance has been an area recent advancement. The vast majority of algorithms rely 
on voxel-based similarity metrics (e.g. mutual information) combined with geometric-
based smoothing parameters (e.g. B-splines) (30, 31). The accuracy of these algorithms 
is often sufficient when contrast is present in the images and the motion is smooth, 
however, recent studies, such as the one illustrated in Figure 2(32), have indicated that 
as contrast is reduced and the motion is complex and non-uniform, the accuracy reduces 
substantially (33-35). In several instances (e.g. contrast-limited images, sliding interfaces) 
biomechanical models have succeeded in achieving the desired level of accuracy (8, 9, 
11, 17, 18, 20, 21). The successful completion of this program of research will expand 
these proven models to model deformation observed between planning and intra-
procedural images for percutaneous ablation (PTA). The development of these models, 
which maintain accuracy regardless of extent of contrast in the images, will enable the 
safe use of deformable registration for PTA guidance (integration of pre-treatment 

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images) and PTA response (e.g. water loss and tissue retraction due to heating and 
inflammation). 
 
 
 
 
 
ELIGIBILITY 
1.6 Inclusion Criteria 
 
1. Patients presenting with ≤ 3 liver tumors (biopsy-proven or documented by imaging) 
measuring 1 to  5 cm planned to undergo percutaneous thermal ablation with either 
microwave or radiofrequency ablation. Patients with more than 3 tumors might also 
be eligible in case other tumors can be treated with another curative-intended loco-
regional therapy (i.e. surgical resection, radiation therapy). 
2. Ability to completely cover the target tumor with at least a 5 mm ablation margin. 
3. Written informed consent to voluntarily participate in the study and follow-up CT scan 
schedule 
4. Age > 18 years-old 
5. Performance status 0-2 (Eastern Cooperative Oncology Group Classification [ECOG]) 
Figure 2. Two methods of dose accumulation were 
evaluated by deforming a gel dosimeter. Morfeus was more 
accurate at representing the actual deformation.  

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6. Target tumor should be visualized on contrast-enhanced CT 
7. Adequate glomerular filtration rate 
1.7 Exclusion Criteria 
 
1. Active bacterial infection or fungal infection on the day of the ablation that, in the opinion 
of the investigator, would interfere with safe delivery of the study procedure or with the 
interpretation of study results.  
2. Platelet < 50,000/mm3.  
3. INR > 1.5 
4.  Patients with uncorrectable coagulopathy.  
5. Currently breastfeeding or pregnant (latter confirmed by serum pregnancy test).  
6. Physical or psychological condition which would impair study participation.  
7. ASA (American Society of Anesthesiologists) score of > 4.  
8. Any other loco-regional therapies at the target lesion(s) within 30 days of the ablation 
procedure. 
 
NUMBER OF PARTICIPANTS 
Preliminary retrospective data on the control arm suggest that a minimum ablation margin 
(MAM) of 2mm (SD 2) is generally achieved when ablation is performed without the use 
of software guidance. A sample size of 50 evaluable subjects in each group will have 80% 
power to detect a difference in means of -1.132 (the difference between a control arm 
mean, of 2 mm and the experimental arm mean of 3.132) assuming that the common 

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standard deviation is 2 using a two group t-test with a two-sided 0.05 significance level.  
Assuming an accrual rate of 35 patients per year, the study accrual duration will be 
around 3 years, with follow-up for at least 2 years, totaling 5 years for the entire study 
duration.  We will have an interim look for superiority once half the evaluable subjects 
(n=50) have been enrolled. A Lan-Demets spending function using an Obrien-Flemming 
boundary will be used for superiority stopping boundaries. We will stop enrollment at the 
control arm at our interim look if our p-value is less than 0.003. East v6.5 was used for 
sample size calculation. The next 50 patients would be enrolled on the experimental arm 
only to allow further development of the proposed biomechanical model on clinical 
practice, as well allow other interventional radiologists at our Department to utilize it. 
We plan to screen 140 subjects and expect approximately 20 subjects to be screen 
failures.  Furthermore, subjects after randomization who drop out due to tumor 
progression, inability to clearly depict target lesions, and major complications precluding 
further ablation will be considered inevaluable.  To account for an expected 20% 
inevaluable subjects, we will enroll a total of 120 subjects to ensure 100 evaluable 
subjects.   
 
STUDY PLAN/DESIGN 
1.8 Method 
RayStation® is a flexible, innovative treatment planning system. It combines 
unique features like unmatched adaptive therapy capabilities, multi-criteria optimization, 

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optimization for HDR brachytherapy and external beam therapy with photons, electrons, 
protons as well as helium and carbon ions. RayStation supports a wide range of 
treatment machines, providing one control center to create biomechanical deformable 
registrations using “Morfeus”.  Morfeus lets the investigators focus all their skill and 
experience on evaluating and refining plan quality.    
To investigate the impact of the proposed biomechanical model on clinical decisions 
during ablation guidance and end-point assessment, patients will be randomized in two 
treatment arms (i.e. experimental arm - including anatomical modeling of the liver, and 
control arm) with a 1:1 ratio. The primary objective is to assess whether applying 
biomechanical models during percutaneous ablation will increase the minimal ablation 
margins, which will be evaluated at the end of the procedure with the proposed software 
on both cohorts. Additionally, two other distinct end-points will analyzed: ability of the 
model to provide tumor identification for ablation probe placement on intra-procedural 
non-contrast enhanced CT, and local tumor control rates achieved with the clinical 
application of this model. Operating physicians will be informed in respect which arm the 
patient was randomized at the time of ablation (figure 3). 
 

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Figure 3: Patient randomization flowchart 
 
A. Impact on tumor targeting 
The clinical trial will be designed according to the optimized parameters from our 
retrospective analysis. The optimized biomechanical models will be used to assess the 
accuracy (e.g. the ability of the model to accurately describe the motion, deformation, and 
volume change and tumor location in the liver between the pre-ablation contrast-
enhanced CT and the intra-procedural non-contrast enhanced CT) in both cohort of 
patients. For the control arm, no information in respect tumor location and targeting will 
be provided for the operating physician during ablation. Imaging processing using the 
biomechanical model will be performed after procedure completion. For the experimental 
A 
B 

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arm, tumor location and confirmation of appropriate targeting with ablation probe will be 
performed intra-procedurally utilizing the proposed software. Differences in tumor 
targeting accuracy between the two cohorts will be evaluated. If the accuracy of the cross 
validation cohort is not statistically significantly different, using a paired Student’s T-test 
based on the preliminary retrospective results with significance defined as a p value of 
less than 0.05, from the initial optimization and validation results, then the model will be 
identified as complete. If the results are statistically worse, as an alternative approach, 
the initial cohort of patients will be used to perform an independent optimization of the 
model. Collaborations with the statistician will ensure that the appropriate power study 
has been performed for the analysis. The completion of this investigation will provide the 
accuracy of the present model in identifying and facilitate targeting of the liver tumors 
eligible for ablation when compared to the currently utilized standard of care tumor for 
tumor identification and targeting. 
 
B. Impact on minimal ablation margins  
A post ablation contrast-enhanced CT will be performed as per standard of care to 
assess the minimal ablation margins. Such assessment is currently performed manually 
using local rigid anatomic landmarks of the liver between the pre-ablation and post-
ablation contrast-enhanced CTs. In this aim, we will evaluate the impact on the use of the 
advanced biomechanical model-based deformable alignment incorporating motion, 
deformation, and ablation-related volume loss in the liver between the pre-ablation 
contrast-enhanced CT and the post-ablation contrast-enhanced CT. The model will 

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automatically generate a minimal ablation margin on a three-dimensional Cartesian plan. 
Such information will be utilized by the operator physician on the experimental arm to 
determine whether additional ablation is needed at a particular region surrounding the 
target tumor using a cut-off of at ≥  5 mm of minimal ablation margins in relation to the 
tumor borders in all planes (treatment arm). The  ≥  5 mm minimal ablation margin will be 
used to account for the margin of error of the software, which is currently 3 mm. 
Frequency of total coverage of the target tumor, minimal ablation margins distance, and  
 
need for re-ablation between the two cohorts will be analyzed to identify the impact of this 
model on intra-procedural decision-making. 
 
C. Impact on local tumor control  
Rates of local recurrence following ablation in the most recent series varies from 
20% to 45%. Although re-ablation on a different session is a feasible option in a minority 
of patients with recurrence at the ablated tumors, this incurs several disadvantages 
associated with the need to undergo another invasive procedure such as emotional 
stress, increased exposure to complications related to anesthesia and ablation 
procedure, radiation exposure, additional use of intravenous contrast media, and 
 
Figure 4: Image fusion of pre- and post-ablation contrast-enhanced 
CT using the proposed biomechanical model-based deformable image 
registration (Morfeus). Blue line: deep learning-based segmentation of 
the liver; Red line: gross-tumor volume (GTV) contouring; Green line: 
gross-ablation volume. A minimal ablation margin of < 5 mm was 
detected on the latero-posterior aspect of the GTV (arrow). 

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increased associated costs. Given the complex volumetric and spatial changes of the liver 
post-ablation, the ability to map the previous treatment onto the new treatment plan is 
critical not only to avoid treatment related toxicities, but also to ensure that the patients 
receive adequate treatment with optimal coverage. We hypothesize that the use of this 
current model might improve local tumor control rates at 2-years follow-up. The 
completion of this aim will evaluate our hypothesis that the applied biomechanical model 
will improve local tumor control at 2-year when compared to the standard of care control 
arm.  
 
 
           Note: Final Analysis (n = 100 evaluable subjects) 
Figure 5: Clinical Trial schema                 

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1.9 
Collecting Time Points
 
 
 
Legend: SOC: Standard of care (data collected as available per standard of care) 
 
PROCEDURE TO OBTAIN CONSENT 
The patients will be approached by either the Interventional Radiology Faculty or 
Research Staff, including research nurses and research coordinators.  The principal 
investigator or designee who are licensed as physician in the state of Texas will obtain 
informed consent of participants prior to their procedure.  During the consenting process 
patients will be educated and consented for their research participation in this study. 
The study will follow the Office of Research SOP04 – Informed Consent Process. 
PATIENT INFORMATION AND CONFIDENTIALITY PLAN 
Confidentiality will be maintained throughout the study.  An informed consent will 
be obtained prior to the percutaneous ablation procedure.  No identifying information will 

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be used in any publication from this study.  Patient identifiers will be available only to 
the investigators for the study and will be kept in a password-protected database and 
locked file cabinet.  Unique patient identifiers will be used to replace patient name and 
medical record number.  Paper records (data forms, list of patient names and unique 
identifiers), will be kept in a locked file cabinet with access granted only to study 
investigators.  In the conclusion of the study, patient identifiers will only be maintained 
with the principal investigator to allow future review of the research. The protected 
health information used in this study will not be reused, nor will it be used for other 
research.  As this is a prospective study, an informed consent will be obtained and 
authorization to use and disclose protected health information is requested.  
  
Morfeus, a software-aided imaging application, is located within MD Anderson 
password protected behind the institutional firewall with access only granted to authorized 
study investigators.  Morfeus will be provided at no cost to the study participants.  There 
is no foreseeable injury or risk to subjects using Morfeus.  Participants may withdraw from 
the study at any time for any reason and are not obligated to reveal their reasons for 
withdrawal, the data and test results already collected will be kept and may be used.  All 
study data will be stored in password-protected computers and/or locked file cabinets and 
will continue to be stored securely after the study. 
 
STATISTICAL CONSIDERATIONS 
Statistical Design 

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The primary endpoint is to assess whether applying biomechanical models 
increase the minimal margins of ablated lesions properly covered by ablation on a 
three-dimensional analysis. The secondary endpoints of our study will compare the two 
arms in respect local and systemic oncological outcomes following liver ablation, 
procedure-related complications, and quality of life via a quality of life (QOL) 
questionnaire. Specifically, we will analyze the 2-years local tumor progression free-
survival rates at the ablated lesions. On the experimental arm, we will evaluate the 
impact of software use on procedure workflow as well user’s experience. 
Statistical Methods 
A. Analysis Plan 
Statistical analysis of this study will be the responsibility of the principal 
investigator (PI) and statistician. The PI and statistician will also be responsible for the 
appropriate conduct of an internal review for the final dataset and any study-related 
material to be authorized for publication. 
To assess the effect of applying biomechanical image registration models during 
percutaneous microwave ablation, the primary endpoint of this intent-to-treat 
randomized trial will be on the impact of the software use on the minimal margins of 
ablated lesions properly covered by ablation on a three-dimensional analysis. Patients 
will be evenly randomized (i.e., 1:1 ratio) to two treatment arms (i.e. experimental arm - 
including anatomical modeling of the liver, and control arm) using the Pocock-Simon 
dynamic allocation method to balance the baseline covariates: tumor histology 

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(colorectal vs other histologies), RAS mutation (for colorectal only, yes vs. no vs. 
undetermined), lesion size (<2cm, 2.0-3.0cm, >3cm-<5cm), subcapsular location, 
defined as tumor within 1 cm from the liver capsule (yes vs no) and presence of multiple 
lesions (yes vs. no). At the end of the study, the average minimum ablation margins will 
be compared between two arms using a 2-sample t-test (or Wilcoxon rank-sum test).  
The means and corresponding 95% confidence intervals will be reported for both arms 
of the study.   
As a secondary objective, the Kaplan-Meier method will be used to estimate local 
tumor progression-free survival (LTPFS) and 95% confidence intervals for the quantiles 
of the LTPFS function based on the method of Brookmeyer and Crowley will be 
calculate for each arm. Time point probabilities (e.g., 2-year LTPFS) and the associated 
log-log transformed pointwise 95% confidence will also be reported.  A multivariate Cox-
proportional hazards model will be fitted to the data with ablative margin as a 
continuous variable to assess the significance of study arm and ablative margin size on 
LTPFS while simultaneously adjusting for known covariates that effect LTPFS.  LTPFS 
will be measured from date of ablation to earliest date of progression at the ablated 
lesion, death.  Those progression free and alive will be censored at their date of last 
clinic visit.  Similar analysis will be used for 2-years intra-hepatic (progression at any 
site of the liver) progression-free survival and overall survival.   Standard summary 
statistics will be computed for complication rates, quality of life, and liver function and 
compared between arms.  Statistical significance will be defined as p < 0.05.   
 

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B. Randomization 
A dynamic randomization method by Pocock and Simon will be used with a 
minimization probability parameter of 0.90. The randomization process will be controlled 
to ensure a balanced stratification by treatment arm for the factors listed above. Patients 
will be randomized to either experimental arm or no control arm using the Clinical Trial 
Conduct (CTC) website (https://biostatistics.mdanderson.org/ClinicalTrialConduct), 
which is housed on a secure server at MDACC and maintained by the MDACC 
Department of Biostatistics.  Access to the website will be gained through usernames 
and passwords provided by the MDACC Department of Biostatistics to the clinical 
team.  Training on the use of the CTC website to randomize patients on the study will 
be provided by the biostatistical collaborators. This is an open-label trial with stratified 
randomization. When a patient is enrolled on the study, the research nurse or 
coordinator of the study will enter patient's information including medical record number 
and stratification factors.  Through the web interface, after the randomization button is 
clicked, the result of the randomization will be displayed on the screen for users to 
view.  All data on randomization will be stored in a secure SQL server database. 
PROTOCOL MONITORING PLAN 
MD Anderson’s Data Safety Monitoring Board (DSMB) will monitor the conduct of 
the study.  The principal investigator will be responsible for the management of the 
protocol.  Identifiers (name, medical record number) will be collected but will be 
replaced by study numbers in the analytical file.  They key linking these numbers will be 
retained in a locked file by the principal investigator.  All study personnel have 

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completed training in methods of maintaining the confidentiality of health information.  
Electronic records will be stored on password protected institution computers behind the 
institution firewall.  Only the principal investigator and research staff in Interventional 
Radiology will have access to the study.  Data will not be transferred to laptop 
computers that are removed from the institution.  Complete confidentiality will be 
maintained during this evaluation, manuscript preparation and submission.  Information 
from individual Case Report Forms (CRFs) will be saved in an institutionally-based and 
approved electronic database.  Adverse events such as inaccurate tumor localization 
and ablation coverage, as well as subsequent local tumor progression will be captured 
and recorded in OnCore. 
 
DATA COLLECTION PLAN 
All subjects will be registered in OnCore and data will be entered in an UT MD 
Anderson Cancer Center approved electronic database.  The institutionally approved 
database is a secure, web-based application with controlled access designed to support 
data capture for research studies, providing:  1) an intuitive interface for validated data 
entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated 
export procedures for seamless downloads to common statistical packages; and 4) 
procedures for importing data from external sources.  It is hosted on a secure server by 
MD Anderson Cancer Center that has undergone an annual Governance Risk & 
Compliance Assessment by MD Anderson's Information Security Office and found to be 
compliant with HIPAA, Texas Administrative Codes 202-203, University of Texas Policy 

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165, federal regulations outlined in 21CFR Part 11, and UTMDACC Institutional Policy 
#ADM0335. 
Those having access to the data include the study PI and research team 
personnel.  Users are authenticated against MDACC's Active Directory system.  The 
application is accessed through Secure Socket Layer (SSL).  All personal identifying 
information will be removed from the data when it is exported for analysis.   
Following publication, study data will be archived in the electronic database indefinitely, 
since study data may be useful for future research studies performed under separate 
IRB approved protocols. Since this is a secure electronic database with controlled 
access, and because subject identifiers may be needed to link study data to data from 
other sources under future IRB approved protocols, subject identifying information will 
be retained in the archived database.  No specific subject identifiers will be collected in 
this study.  We acknowledge that there is a theoretical chance that the participants may 
be identified from their combined responses to the demographic questions.  However, 
no attempt will be made by the research personnel to identify the survey respondents.  
Also, data will only be reported in aggregate form.  The demographic information in the 
survey, along with all other survey responses, will be stored securely in the database.  
Up to five fully deidentified CT images will be shared with RaySearch Laboratories for joint 
development purposes directly related to the NIH-funded Academic-Industry Partnership R01 
for the COVER-ALL clinical trial and project. RaySearch Laboratories is the industry partner for 
this grant. 
 

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Al-Mayah A, Moseley J, Velec M, Hunter S, Brock K. Deformable image 
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of breathing motion on radiotherapy dose accumulation in the abdomen using 
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QUESTIONNAIRES 
 
Software user’s experience 
Specific Use 
Definition 
Software helped me 
(1: no; 2: somewhat; 
3: yes) 
Comments 
Probe Placement 
Ability to understand 
probe positioning in 
relation to the target 
lesion 
 
 
Ablation 
confirmation 
Evaluating technical 
success of the 
procedure (full 
coverage of the 
tumor) 
 
 
 
 
 
 
 
 
 
 
 

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Procedure Details 
Variable measured 
Definition 
Answer 
Number of probes 
utilized on the target 
lesions 
1 – 3 
 
Number of 
overlapping ablations 
0 – 3 
 
Total duration of 
ablation (counting 
overlaps) 
In minutes (5-20) 
 
Post-ablation 
Contrast-enhanced 
CT after first round of 
ablation? 
Yes/No 
 
Need to re-ablation? 
Yes / no 
 
Number of probes 
utilized on the target 
lesions 
1-3 
 
Number of 
overlapping ablations 
0-3 
 
Total duration of 
ablation (counting 
overlaps) 
In minutes (5-20) 
 
Post-ablation 
Contrast-enhanced 
CT after second 
round of ablation? 
Yes/No 
 
Need to re-ablation? 
Yes / no 
 
Number of probes 
utilized on the target 
lesions 
1-3 
 
Number of 
overlapping ablations 
0-3 
 
Total duration of 
ablation (counting 
overlaps) 
In minutes (5-20) 
 
 

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QUALITY OF LIFE QUESTTIONAIRE 
 

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