A Pilot Study to Determine the Efficacy of Cryoablation for the Treatment of Invasive Breast Carcinoma Following Neoadjuvant Therapy
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: M.D. Anderson Cancer Center

 
 
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A Pilot Study to Determine the Efficacy of 
Cryoablation for the Treatment of Invasive Breast 
Carcinoma Following Neoadjuvant Therapy 
 
 
Study Chair:  
Rosa F. Hwang, M.D. 
Department of Surgical Oncology 
 
Study Co-Chairs: 
Bruno Fornage, M.D. 
Department of Diagnostic Imaging 
 
Gildy V. Babiera, M.D. 
Department of Surgical Oncology 
 
Collaborators: 
Kelly K. Hunt, M.D. 
Department of Surgical Oncology 
 
H. Carisa Le-Petross, M.D. 
Department of Diagnostic Imaging 
 
Amy Zhang, M.D. 
Department of Pathology 
 
W. Fraser Symmans, M.D. 
Department of Pathology 
 
Jason Stafford, Ph.D. 
Department of Imaging Physics 
 
Caimiao Wei, M.S. 
Department of Biostatistics 
 
 
 

 
 
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1 
Introduction 
 
1.1 Background—Cryoablation  
 
1.1.1 Ablation therapies for primary malignant diseases and metastatic disease 
Ablative therapy using image guidance is an established and standard therapeutic technique for 
treatment of metastatic hepatic tumors.  The best described techniques are the applied thermal 
technologies, including radiofrequency (RF) ablation and cryoablation.  RF ablation for hepatic 
metastases from colorectal metastases can achieve local tumor control [1] and 5 year survival 
rates as high as 30%.[2]  The same techniques have been applied to renal cell carcinoma but 
long-term follow-up data is lacking.[3, 4]   The failure of these ablative therapies to extend long-
term survival is not due to any inherent failure of the ablation technique to destroy the targeted 
focus of cancer but rather due to the nature of hepatic metastases and the propensity for 
multifocal disease. 
Ablation therapies are currently being investigated in the treatment of primary tumors of many 
organ sites including prostate, renal cell carcinoma and lung cancer.  The American College of 
Surgeons Oncology Group (ACOSOG) protocol “A Pilot Study of Radiofrequency Ablation in 
High-Risk Patients with Stage 1A Non-Small Lung Cancer” is an active study designed to 
evaluate the role of RF ablation in the treatment of primary lung cancer. 
1.1.2 Cryoablation for benign fibroadenomas 
Non-operative ablation of breast lesions is also a well studied area of investigation.  The clinical 
model for breast cancer ablative therapy exists in the current office-based practice of 
cryoablation for benign fibroadenomas.  These tumors are detected through physical 
examination or mammographic screening.  After a core biopsy is performed to establish the 
diagnosis, the cryoablation technique can be employed as definitive treatment.  This involves an 
injection of local anesthetic into the skin followed by a small nick in the skin for placement of the 
cryotherapy probe.  The 3 mm probe is then inserted and the probe tip is guided to the center of 
the tumor under ultrasound guidance.  The freezing process is created by liquid nitrogen gas 
circulating within the probe.  To achieve complete ablation the freezing process is repeated for a 
total of two freeze-thaw cycles.  The entire cryoablation process takes about 20 minutes.  Once 
complete, the probe is withdrawn and a bandaid is applied over the insertion site.  The patients 
are then followed to document absorption of the fibroadenoma.  Complete clinical 
disappearance (by physical examination, ultrasound and mammogram) of fibroadenomas is 
achieved within one year in 95% of patients.[5, 6] In many centers, cryoablation of 
fibroadenomas is the preferred practice over surgical excision for several reasons, including the 
convenience of using the common office-based imaging system of breast ultrasound (US).  As 
such US-based cryoablation is available to all practitioners equipped and certified in breast 
ultrasound.  Furthermore, cryoablation is preferred by patients as it produces less pain, requires 
only a local anesthetic and leaves a much smaller incision than surgical excision.  Once the skin 

 
 
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is anesthetized, the procedure is essentially painless due to the anesthetic properties of freezing 
the tumor.  Thus, most patients undergo the cryoablation treatments fully awake without 
sedation and with minimal local anesthetic. Tumors amenable to cryoablation can be visualized, 
localized, and treated in real-time, typically in the span of 20 minutes.  Cryoablation of 
fibroadenomas is also cosmetically advantageous since the treatment does not require removal 
of normal surrounding breast tissue and there is restoration of normal or near normal breast 
architecture on physical examination as well as by imaging with both ultrasound and 
mammography.[5, 6]  The same advantages would be expected for cryoablation of primary 
breast cancers.  
1.1.3 Cryoablation for invasive breast cancer 
The use of ablative technologies, including RF ablation, cryoablation, interstitial laser therapy, 
microwave thermotherapy, and focused ultrasound (FUS) ablation are presently being explored 
to treat breast cancers as an alternative to surgical resection.[7-24]  Although the above 
described ablative therapies could be considered for study, this application focuses on 
cryoablation for several reasons.  One of the goals of this trial is to explore non-operative, office-
based options to treat primary breast cancer.  Toward that end, the ablative technique should be 
simple, readily available and as painless as possible.  As mentioned previously, cryoablation for 
fibroadenomas serves as a useful model as it is easily performed in the office with minimal 
discomfort.  The availability of office-based breast ultrasound and the short time for treatment 
with cryoablation are advantageous over other technologies such as  radiofrequency, laser, 
focused-US, and microwave ablation which generally require additional imaging (stereotactic 
mammography or breast MRI), require longer treatment times for complete ablation (up to 2 
hours) and typically produce more discomfort requiring sedation and/or anesthesia support.   
To replace surgical resection of primary breast tumors with cryoablation, complete tumor 
ablation must be performed with a high rate of success.  There are technical aspects of the 
cryoablation procedure that are important to optimize the complete ablation.  The first is the 
ability to reliably localize the tumor for ablation.  Many breast interventionists are familiar with 
US localization of tumors and there are existing guidelines for US credentialing that provide a 
ready-made approach for protocol standardization.  This protocol will use established 
techniques employed in the cryoablation of fibroadenomas, but these techniques will be 
scrutinized for improvements during this study with the goal of achieving optimal ablation 
success. 
To date, results from cryoablation of breast cancers have been highly successful with complete 
cell death seen within the targeted ablation zone.  A pilot study of cryoablation in 27 patients 
with primary breast cancer documented complete ablation in those with infiltrating ductal 
carcinoma measuring less than 1 cm and in those with infiltrating ductal carcinoma measuring 
less than or equal to 1.5 cm without an extensive intraductal component.  In this report, 
cryoablation was performed prior to surgical resection and the zone of ablation was evaluated 
with standard pathologic assessment.  Of these patients, 25 out of 27 had a sentinel node 
biopsy performed at the same setting without interference from the cryoablation. [25]  While this 

 
 
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data is highly promising, larger multi-institutional studies are needed to explore cryoablation in 
the treatment of primary breast cancer.  This concept is currently being explored by ACOSOG 
for women with T1, unifocal breast cancers (ACOSOG Z1072).  Standards have been 
developed for all of the multidisciplinary team members and will be incorporated into the current 
trial. 
Reports of other ablative technologies for the treatment of breast cancer have demonstrated 
incomplete ablation in up to 30% of cases on pathologic assessment.[7-24]  MRI pre- and post-
ablation was shown in one study to predict residual disease in a pilot study of RF ablation for 
breast cancer followed by surgical resection.[26]  The ability of MRI to assess completeness of 
ablation following cryoablation is a component of the current trial. 
In the management of metastatic hepatic tumors, multiple ablation treatments are often required 
to achieve complete ablation and local control.  It is possible that a similar paradigm may be 
applicable if cryoablation technology is applied to the treatment of locally recurrent primary 
breast cancers, larger primary breast cancers or to the treatment of residual foci of primary 
breast cancer after neoadjuvant chemotherapy. 
1.1.3.1 American College of Surgeons Oncology Group (ACOSOG) Z1072 
ACOSOG-Z1072 is phase II trial intended to determine if cryoablation can be successful at 
ablating small homogeneous tumors in a treatment-naïve breast.  This is the important first step 
to determining whether there is feasibility of using cryoablation in any breast cancer 
circumstance as well as to determine the efficacy and accuracy of imaging with MRI.  This trial 
continues to accrue patients, including women at our institution, and the results have been 
excellent with high rates of complete ablation and concordance between MRI findings and 
surgical pathology.  The co-investigators and collaborators for the current trial are comprised of 
the same team that is participating in the ongoing ACOSOG Z1072 trial. 
1.1.4 Neoadjuvant chemotherapy (NCT) 
 
1.1.4.1 Rationale 
One of the major reasons that NCT has become widely accepted as the treatment of choice for 
patients with locally advanced breast cancer is that it improves the surgical options for patients 
by downsizing the primary tumor.  The frequency of mastectomies has decreased in patients 
receiving NCT with no significant increase in the in-breast recurrence rates.[27] 
1.1.4.2 Downsizing tumors with NCT 
Although there is no clear consensus regarding the optimal regimen for neoadjuvant therapy, 
the literature indicates that combination therapy is superior to single agent therapy.  Moreover, 
sequential regimens, in which multiple drugs are administered in a preplanned sequence with 
no breaks, are associated with increased pathologic complete response (pCR) rates.[28]  At our 
institution, the objective response rate (ORR, complete and partial responses) was 95% with 

 
 
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paclitaxel x 4 followed by 5-fluorouracil, epirubicin and cyclophosphamide (FEC) for 4 cycles.  
The pCR rate with this regimen was 26.3%.  When trastuzumab is added to this regimen in 
patients with HER-2-positive disease, the pCR rate increased to 65.2%.[28]  Correspondingly, 
the rate of breast conserving surgery (BCS) was also higher than would be expected in this 
group of patients with stage II-IIIA cancers (52.6-56.5%).[28]  [27, 29] 
A prospective, multicenter, randomized phase III study was conducted by the NSABP with a 
secondary endpoint to analyze the feasibility of breast BCS following NCT.  For patients with T2 
or greater invasive breast cancers treated with doxorubicin plus docetaxel or doxorubicin plus 
cyclophosphamide followed by docetaxel, the rate of BCS was 74%.  Factors associated with a 
significantly higher rate of BCS included postchemotherapy tumor size ≤ 20 mm, nonlobular 
histology and treatment in a larger center (>10 enrolled patients). 
1.1.5 Margin status with BCS after NCT 
Resection of breast cancer with negative margins is an essential component of achieving 
optimal local control and is a significant factor in minimizing the risk of ipsilateral breast tumor 
recurrence[30].  Preoperative treatment of breast cancer with chemotherapy often results in 
downsizing with a reduction in the size of the primary tumor that can be identified on imaging, 
including mammogram, ultrasound and MRI.  Multiple studies have demonstrated that there is 
no statistical difference observed for margin involvement between patients treated with NCT 
compared to those treated initially with surgery (21% vs. 18%, p=0.52)[31].  Resection of 
invasive lobular carcinomas treated with NCT was a risk factor for positive margins compared to 
resection of invasive ductal cancers and therefore, lobular carcinomas are excluded from the 
current protocol.  At our institution, between 1987 and 2000, 340 patients were treated with NCT 
followed by BCS and 4%  had positive surgical margins.[32].  Five year rates of IBTR-free and 
LRR-free survival were excellent at 95% and 91%, respectively.  Variables that correlated with 
IBTR and LRR were clinical N2 or N3 disease, pathologic residual tumor greater than 2 cm, a 
multifocal pattern of residual disease and lymphovascular space invasion.  Tumor histology was 
not analyzed in this series as a predictor of positive margins or locoregional recurrence-free 
survival.  
Various imaging modalities have been evaluated for their ability to predict residual tumor after 
neoadjuvant therapy.  MRI has been reported to have very good sensitivity, specificity and 
accuracy in detecting residual disease (90.5, 100, and 91.3%).  In a series of 45 patients, the 
correlation coefficient between MRI and pathology measurements of the residual primary tumor 
was excellent (r2 0.966, p<0.0001).[33]  However, in a smaller series of 17 patients treated with 
NCT followed by surgery, MRI actually overestimated the extent of residual disease.  
Discordance between MRI and pathologic evaluation (<0.5-cm difference in size of residual 
tumor) was found in 66.6% of patients who had pathologic complete, or near-complete, 
response.[34]  In the current protocol, FNA and/or core biopsy of the residual primary tumor site 
will be required to confirm residual carcinoma prior to cryoablation.  Compared to physical 
exam, mammography and ultrasound, MRI has the highest accuracy in assessing the degree of 
pathologic response (19%, 26%, 35% and 71%, respectively, p<0.002).[35]  [36] 

 
 
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1.2 Objectives 
 
1.2.1 Primary Objective 
 
To determine the rate of complete tumor ablation in patients treated with cryoablation, with 
complete tumor ablation defined as no remaining invasive or in situ carcinoma present upon 
pathological examination of the targeted lesion. 
 
1.2.2 Secondary Objectives 
 
To evaluate the negative predictive value of MRI in the post-ablation setting to 
determine residual in situ or invasive breast carcinoma  
 
To describe the adverse events associated with cryoablation 
 
To prospectively gather pain assessment data on cryoablation and surgical resection 
 
Explore technical variables that may affect success of cryoablation 
 
1.3 Study Design 
This is a phase II non-randomized pilot study.  Following neoadjuvant chemotherapy, all fully 
eligible and registered patients will undergo imaging by mammography, ultrasound, and breast 
MRI.  Patients will then be treated with cryoablation therapy followed by re-imaging with breast 
MRI.  Patients will then undergo complete surgical resection of the primary tumor. 
Excised tissue will be evaluated pathologically for residual invasive disease in the targeted 
lesion.  All patients will have standard surgical staging of the axilla with sentinel node dissection 
or axillary dissection and will have adjuvant therapy (hormonal therapy, chemotherapy and 
radiation therapy) as appropriate based on the initial stage of the disease. 
1.4 Accrual Goal 
A total of 10 eligible and evaluable patients are required for analysis.  If results of the pilot study 
are encouraging and indicate that the study is feasible (see Statistical Considerations, section 
12), we will plan a larger study to definitively evaluate the role of cryoablation. 
 
1.5 Schema 
 

 
 
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2 
Patient Selection 
Each eligibility criterion must be evaluated and documented in the patient’s medical record.  
Patient eligibility must be determined by the investigator. 
 
2.1 
Eligibility Criteria 
A patient will be eligible for inclusion in this study only if ALL of the following criteria apply.  
1. Unifocal primary invasive ductal breast carcinoma diagnosed by core needle biopsy. 
NOTE: Patients with lobular carcinoma, multifocal and/or multicentric ipsilateral breast 
cancer, multifocal calcifications, or DCIS with microinvasion are NOT eligible. Patients 
with contralateral disease will remain eligible.  
2. No history of open surgical biopsy and/or lumpectomy for diagnosis/treatment of the 
index breast cancer.  Note: Prior rotational and/or vacuum-assisted core biopsies are 
permitted if no significant distortion is seen on imaging that could obscure visualization 
and detection of residual disease on MRI, or visualization of cancer on ultrasound for 
cryoablation procedure. 
3. Neoadjuvant chemotherapy or hormonal therapy for the index tumor is required. 
4. Residual tumor size < 2.0 cm in greatest diameter.  Specifically, the tumor must measure 
< 2.0 cm in the axis parallel to the treatment probe and < 1.5 cm in the axis anti-parallel 
to the treatment probe.  Largest size measured by mammogram, ultrasound or MRI will 
be used to determine eligibility. 
5. Tumor enhancement on pre- registration MRI.  
6. Tumor with <25% intraductal components in the aggregate. 
7. Adequate breast size for safe cryoablation.  Male breast cancer patients and female 
breast cancer patients with breasts too small to allow safe cryoablation are not eligible 
as the minimal thickness of the breast tissue does not lend itself to cryoablation. 
8. Patients with prior in-situ or invasive breast carcinomas are eligible if the prior 
carcinomas occurred in the contralateral breast.  Patients with prior in-situ or invasive 
carcinomas of the ipsilateral breast are not eligible. 
9. Non-pregnant and non-lactating. Patients of childbearing potential must have a negative 
serum or urine pregnancy test. NOTE: Peri-menopausal women must be amenorrheic 
for > 12 months to be considered not of childbearing potential.  
10. Patient has no contra-indication to an MRI examination, such as clips/prostheses/ 
implants that are not MRI compatible, or compromised renal function, with a measured 
or calculated glomerular filtration rate of 60ml/min/1.73m2. 
11. Patients less than 18 years of age will not be included in this study. 
 
2.2 
Staging Criteria 
Patients will be staged according to the staging criteria adapted from the American Joint 
Committee on Cancer (AJCC) Cancer Staging Data Forms of the AJCC Cancer Staging 
Manual, 7th Edition, 2010. 
 

 
 
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2.3 
Study Calendar 
 
Pre-neo 
adjuvant 
chemo 
therapy 
Near 
Completion 
of chemo 
therapy 
Post 
Chemo 
 
Prior to 
Cryoablation* 
Within 30 
days post 
registration 
Within 14-
28 days 
post-cryo 
Within 28 
days 
post-cryo 
Within 14 
days post-
surgery 
History and 
Physical 
 
 
INFORMED CONSENT/ 
REGISTRATION 
X 
CRYOABLATION 
X 
SURGERY 
X 
Pregnancy 
Test 
 
 
X1 
 
 
Ipsilateral 
mammogram 
 
X 
 
 
 
Hematology 
 
 
X2 
 
 
Ipsilateral 
breast 
ultrasound 
 
X 
X3 
 
 
Breast MRI 
 
 
X4 
X 
 
Core biopsy 
X5 
 
 
 
 
U/S guided 
FNA/Core 
biopsy of 
residual tumor 
 
 
X6 
 
 
Pathology 
assessment 
 
 
X 
 
X 
*     Within 45 days prior to registration unless otherwise specified.  
1. For women of childbearing potential only. 
2. ANC ≥1500/uL and platelets > 50,000/uL 
3. For Ultrasound-guided FNA and/or core biopsy. 
4. Baseline MRI must be done within 14 days prior to registration. 
5. Core biopsies for tissue diagnosis and tumor markers including ER, PR, and HER-2/neu, will be performed 
prior to registration. (Standard of Care) 
6. FNA and/or core biopsy of residual tumor must confirm diagnosis of carcinoma. 
Note: All procedures before informed Consent and the first MRI are Standard of Care.  
 
2.4 
Testing Guidelines 
 
2.4.1 Core biopsy (pre-neoadjuvant chemotherapy) 
The patient must have a prechemotherapy biopsy confirming the diagnosis of invasive ductal 
breast cancer.  Results of ER, PR and HER-2/neu must be obtained on the core biopsy 
material. 
The presence of in situ and invasive ductal carcinoma and approximate relative proportion of in 
situ component must be recorded.  The Nottingham Grade Scheme incorporating the degree of 
tubule formation, nuclear grade and mitotic activity, should be used for invasive carcinoma.  The 
in situ tumor should be described in terms of architectural type (solid, cribiform, etc.) nuclear grade 
and presence of luminal necrosis, and calcifications. 

 
 
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2.4.2 Fine needle aspiration (FNA) and/or Core biopsy (pre-registration) 
Prior to registration, an ultrasound-guided FNA and/or core biopsy of the residual area of 
disease seen on imaging studies after neoadjuvant therapy must be performed to confirm 
carcinoma.  If no residual carcinoma can be confirmed, then the patient is not eligible for the 
study. 
2.5 
Magnetic Resonance Imaging 
A standard-of-care bilateral breast MRI examination will be performed pre-registration to 
evaluate the extent of the tumor and multifocality, and to compare areas of segmental or 
regional enhancement in each breast.  
 
2.5.1 Required Imaging Sequences 
The examination protocol of both breasts should contain at a minimum the following sequences: 
 
Bilateral pre-contrast axial T1-weighted 3D fast spoiled gradient echo pulse 
images with fat saturation (≤ 2 mm slice thickness, no gap), 
 
Bilateral three post-contrast series of axial T1-weighted 3D fast spoiled gradient 
echo images with fat saturation (≤ 2 mm slice thickness, no gap) with the first 
post-contrast  series obtained immediately after intravenous injection of 
gadolinium (at T0) 
 
A delayed sagittal T1-weighted 3D fast spoiled gradient-echo pulse sequence 
with fat suppression (2-4mm slice thickness, no gap). 
 
A diffusion-weighted imaging sequence. 
 
2.5.2 
Contrast Medium 
The intravenous dose gadolinium contrast media should be 0.1 mmol per kilogram of body 
weight, given via a power injector at a rate of 3 mL/sec, followed by a 20-mL saline flush. 
2.5.3 
Image Interpretation 
Interpretation of the MRI exams will be according to the categories established in the American 
College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) for MR 
Imaging. (American College of Radiology. ACR breast imaging reporting and data system (BI-
RADS): breast imaging atlas. Reston, Va: American College of Radiology, 2003). 
Areas of enhancement classified as suspicious for malignancy not contiguous with the main 
tumor on preregistration scan must be found to be benign by histology for the patient to be 
eligible for the study.  Assessment by ultrasound-guided or MRI-guided biopsy is acceptable 
with concordant results. 
 
 

 
 
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3 
Patient Registration 
 
The patient or the patient’s legally acceptable representative must provide a signed 
and dated informed consent prior to registration and prior to beginning any study–
related procedure or intervention.  
 
4 
Interventions 
 
4.1 
Tumor Cryoablation 
All registered patients will receive cryoablation of the index breast cancer within 4 weeks after 
the last dose of chemotherapy.  Only the devices and procedures described in the sections 
below may be used for patients registered to this study. 
 
4.1.1 Cryoablation Device 
The cryoablation will be performed using the commercially available Visica 2™ 
Treatment System. The Visica 2™ Treatment System (Sanarus Technologies, Inc.) 
consists of a Visica 2 Console, Visica 2 ICE Probe(s) and associated liquid nitrogen 
(cryogen) Case Dewars. The Visica 2 Console is a self-contained unit, which features an 
easy-to-use interface for complete control and monitoring of the cryoablation procedure. 
The Console operates off of standard 120 VAC (60Hz) power. The Visica 2 ICE Probe is 
a single-use, disposable probe designed for use with the Visica 2 Treatment System. 
The primary components of the Visica 2 ICE Probe consist of a surgical stainless steel 
probe with an integrated T-Type Thermocouple for internal temperature measurements. 
There are two configurations of the Probe – the Visica 2 ICE Probe and the Visica 2 ICE  
Probe SL. Only the Visica 2 ICE Probe will be used in this study.  
In accordance with its FDA market clearance, the Visica 2 Treatment System is indicated 
for use in general surgery, gynecology and oncology. The system is designed to destroy 
tissue by the application of extremely cold temperatures. In addition, the system is 
intended for use in the following indications: 
 
General Surgery 
 
 
Ablation of breast fibroadenoma 
 
Localization of breast lesions 
Gynecology 
 
Ablation of malignant neoplasia or benign dysplasia of the female genitalia 
Oncology 
 
Ablation of cancerous or malignant tissue 
 
Ablation of benign tumors 
 
Palliative intervention 

 
 
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Although this study will evaluate the cryoablation of cancerous tissues, it is important to 
understand that ablation will be followed by surgical resection in all cases.  As such, 
cryoablation will not serve as a definitive therapy.  Definitive cancer therapy, inclusive of surgical 
resection and further treatment (e.g. radiation therapy and adjuvant hormonal or chemotherapy), 
are at the treating physician’s discretion, per the standard of care. 
4.1.2 Device Specifications 
Visica 2™ ICE  Probe 
Overall length  
 
 
8 ft. 6 in. nominal  
Shaft Diameter 
 
 
3.4 mm (0.134 in.) 
 
Shaft Length  
 
 
13 cm nominal  
Shaft Active Freeze Zone               
Distal 4.5 cm of Probe Shaft 
Shaft Insulation 
                   
Proximal portion vacuum insulated  
Visica 2™ Console 
Height  
 
 
 
60 in. nominal  
 
 
 
Width  
 
 
 
20 in. nominal  
 
 
Depth  
 
 
 
27 in. nominal 
Weight                        
 
250 lbs. 
 
 
 
 
 
Electrical 
 
 
 
120 VAC (60 Hz) 6 Amps 
 
4.1.3 Device Operation 
The Visica 2™ Treatment System uses a closed system to circulate liquid nitrogen within the 
probe tip creating sub-freezing temperatures that result in precision cryoablation of the intended 
target tissue. After the target lesion has been appropriately identified, the Probe is placed under 
ultrasound guidance into the center of the lesion and cryoablated according to a predetermined 
freeze algorithm consisting of a freeze cycle followed by a thaw cycle, followed by a final freeze 
cycle. The probe is then warmed by an internal electrical resistance heater and removed from the 
patient.  
For the purposes of this study, the Visica 2™ Treatment System will be operated in accordance 
with the Visica 2™ Treatment System Operator’s Manual and Visica™ 2 ICE Probes Instructions 
for Use except for:  
 
 
the collection of specific clinical and device operational information and  
 
the use of a treatment freeze algorithm designed to ablate the target lesion and a margin of 
tissue, analogous to the surgical margins of a lumpectomy.  
 
4.1.4 Cryoablation Procedure 
The cryoablation procedure will be performed in accordance with the instructions outlined in the 
Visica 2TM  ICE Probe Instructions for Use except for:  

 
 
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 
the collection of specific clinical and device operational information, and 
 
the use of the treatment freeze algorithm in Table 1.  
 
Representative sonographic images from the cryoablation procedure will be submitted for 
review by the study radiologist.  
4.1.5   Probe Positioning Procedure -Locate the target lesion to be ablated using 
high resolution real-time ultrasound in both the radial and antiradial projections.  
1) Determine the maximum diameter of the lesion in both projections.  Record maximum 
lesion diameter on the Case Report Form (CRF).  Maximum lesion diameter must be ≤ 2.0 
cm and the maximum lesion width dimension must be ≤ 1.5 cm to be eligible for inclusion 
into the study. 
2) Utilizing sterile technique and local anesthesia, a cryoprobe will be inserted percutaneously 
through a small skin incision (approximately 3-5mm). The probe will be manipulated under 
real-time ultrasound guidance and the probe tip advanced through the center of the 
malignant lesion such that the length of the probe 
shaft penetrates and is centered in the longest 
imaged lesion plane, as measured above. Proper 
probe placement will be documented with 
longitudinal and transverse sonographic imaging.  
3) Visualize the lesion in the anti-parallel axis 
relative to probe shaft (i.e., viewed in cross 
section “end on”). Document probe position within 
the target lesion with an image printout including: 
 
The maximum width dimension shown in that 
plane.  The tumor must measure 1.5 cm or less 
in the anti-parallel axis relative to the probe 
shaft. Record this measurement on the CRF. 
 
Maximum radius (4b) from the probe shaft to the 
outermost edge (farthest edge from probe tip) of 
the target lesion.  This measurement should be 
less than 0.75 cm.  Record this measurement 
on the CRF. 
 
Print out an image showing both recorded width dimensions above.  One or two prints 
may be produced, but both measurements must show on the print(s). 
4) Calculate the maximum lesion width dimension to be ablated as 2x the maximum radius as 
measured above. If the calculated maximum lesion width dimension to be treated (anti-
parallel to probe within the target lesion) is greater than 1.5 cm, the probe must be 
relocated more central to the middle of the lesion.  
5) Use that calculated lesion width dimension to apply the treatment algorithm in Table I if the 
calculated maximum lesion width dimension is ≥ the largest imaged pre-biopsy lesion width 
on either mammogram, ultrasound or MRI.  If the largest imaged pre-biopsy lesion width on 
either mammogram, ultrasound or MRI is larger than the calculated lesion width dimension 
imaged at the time of the cryoablation, use the pre-biopsy lesion width to determine which 
algorithm should be used. 
 
Maximum width 
dimension  
Probe 
Shaft Tip 
Max. Radius 
(4b)  

 
 
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6) When the probe has been centered adequately, 
view the lesion in the long axis plane, parallel to 
the probe shaft and measure the following:   
 
The maximum lesion dimension shown in that 
plane.  This dimension should not exceed 2.0 
cm in the axis parallel to the probe shaft.  
Record this measurement on the CRF. 
 
The distance of the probe tip beyond the distal 
lesion edge.  Enter the maximum lesion 
dimension into the V2 Console.   The Console 
will calculate the distance of the probe tip 
beyond the lesion (7b) to ensure that the probe 
is properly positioned. 
 
Record this measurement on the CRF and print 
out an image of this measurement. 
 
Print out an image showing both recorded 
dimensions above.  One or two prints may be 
produced, but both measurements must show on the print(s). 
7) Initiate freeze cycles. Treatment Algorithm selected in Table 1.  Look at the time listed in 
the second Freeze cycle in order to confirm that the freeze time is set to either 6 or 8 
minutes as referenced in the algorithm. 
8) Record Treatment Algorithm on the CRF. 
9) Monitor ice ball growth using ultrasound visualization.  
10) At the end of HI freeze 1, document maximum ice ball length and width with a printout 
(including measurements on the print).  Record these dimensions on the CRF. Ensure that 
the ice ball diameter exceeds the calculated maximum lesion width dimension by 10 mm on 
all sides as determined via ultrasound by extending the HI freeze time if necessary. Record 
additional HI freeze time and document maximum ice ball length and width with a print out 
(including measurements on the print) if additional freeze time is required.   
11) At the end of HI freeze 2, document maximum ice ball length and width with a printout 
(including measurements on the print).  Record these dimensions on the CRF.  Ensure that 
the ice ball diameter exceeds the calculated maximum lesion width dimension by 10 mm on 
all sides as determined via ultrasound by extending the HI freeze time if necessary. Record 
additional HI freeze time and document maximum ice ball length and width with a print out 
(including measurements on the print) if additional freeze time is required.   
12) After completion of the cryoablation, the probe will be warmed and removed from the 
breast. 
 
 
 
 
 
 
Max. Dimension
Probe tip 
beyond lesion 
(7b) 
Probe 
shaft 

 
 
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Table 1:  Treatment Algorithm 
Max. Width 
Diameter 
< 1.0 cm 
1.0-1.5 cm 
1st 
Freeze 
HI  6 min 
US measure and ensure 
10 mm margin 
HI 8 min 
US measure and ensure 
10 mm margin 
THAW 
10 min 
10 min  
2nd 
Freeze 
HI 6 min 
US measure and ensure 
10 mm margin 
HI 8 min 
US measure and ensure 
10 mm margin 
 
5 Magnetic Resonance Imaging (Post-cryoablation) 
A research breast MRI examination will be performed within 14 to 28 days post-ablation 
to determine whether any residual tumor can be defined within the targeted lesion. 
The cost of the post-ablation MRI will be reimbursed using research funds.  
Required Imaging Sequences 
 
Bilateral pre-contrast axial T1-weighted 3D fast spoiled gradient echo pulse 
images with fat saturation (≤ 2 mm slice thickness, no gap), 
 
Bilateral three post-contrast series of axial T1-weighted 3D fast spoiled gradient 
echo images with fat saturation (≤ 2 mm slice thickness, no gap) with the first 
post-contrast  series obtained immediately after intravenous injection of 
gadolinium (at T0) 
 
A delayed sagittal T1-weighted 3D fast spoiled gradient-echo pulse sequence 
with fat suppression (2-4mm slice thickness, no gap). 
 
A diffusion-weighted imaging sequence. 
A 1.5 Tesla strength or higher magnet and dedicated breast coil should be used. 
5.1 
Contrast Medium 
The intravenous dose gadolinium contrast media should be 0.1 mmol per kilogram of 
body weight, given via a power injector at a rate of 3 mL/sec, followed by a 20-mL 
saline flush. 
5.2 
Review of Ultrasound and MRI Images 
The pre-registration and post-cryoablation MRI images of the affected breast and 
ultrasound images from the cryoablation procedure will be transmitted to the study 
radiologist after the post-cryoablation visit.  
 
 

 
 
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5.2.1 
Image Submission 
The following materials will be submitted to the study radiologist.   
 
Pre-registration and post-cryoablation MRI images of the affected breast . 
 
Ultrasound images from the cryoablation procedure, including images of probe 
placement parallel and anti-parallel to the probe, and images of the largest 
dimension of the ice ball at the end of each freeze cycle, representing the 
ablation zone. 
 
Copies of corresponding radiology reports. 
 
5.2.2 
Final Imaging Review 
The sonographic images of all cases will be compared to the MRI images by radiologist 
HL at the conclusion of the recruitment. The following data from the pre-registration 
MRI images will be recorded:   
 
Index cancer shows enhancement (yes/no) 
 
Maximal size of lesion (cm) 
 
Location of lesion (o’clock, cm from nipple) 
 
Other areas of suspicious enhancement (yes/no, number) 
 
Maximal size of lesion (cm) 
 
Location of lesion (o’clock, cm from nipple) 
The following data from the post-cryoablation MRI images will be recorded:   
 
Cryoablated lesion shows enhancement (yes/no) 
 
Suspicious for residual disease (yes/no) 
 
Consistent with post-treatment change (yes/no) 
 
Indeterminate for residual disease (yes/no) 
Each MRI study (pre-registration and post-cryoablation) and its interpretation will be 
reviewed and evaluated by the designated study radiologist, who will be blinded to the 
surgical and pathologic information.  
Any enhancement in the ablated target lesion on the post-ablation scan similar to that 
seen on the pre-ablation scan will be considered as residual disease for purposes of 
interpreting the MRI exam.  
6 
Surgical Resection 
At the time of surgical resection the surgeon will perform sentinel lymph node 
dissection and/or axillary dissection as per standard of care.  
The surgeon will excise the ablation zone with standard technique.  Additional surgical 
resection (i.e., re-excision or mastectomy) and further treatment (e.g., radiation therapy 
and adjuvant hormonal or chemotherapy) are at the treating surgeon’s discretion as per 
the standard of care. 

 
 
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6.1 
Pathology of Surgical Specimen 
The surgical resection specimen, following cryoablation, will be oriented by the surgeon 
in a manner that facilitates the study of all six margins (lateral, medial, anterior, 
posterior, superior and inferior).  The pathologist will ink the specimen margins and 
serially section the specimen at 2-3 mm intervals in the coronal or sagittal plane (as 
appropriate for the particular specimen) as is standard for breast specimens at our 
institution.  The entire “cryolesion” will be subjected to histological examination.  The 
remainder of the breast tissue will be thoroughly examined, and histological sections 
will be obtained from any grossly abnormal areas as well as from random fibrous areas. 
Reporting of the histological evaluation of the surgical resection biopsy specimen 
should be similar to that of the diagnostic core biopsy specimen (See Testing 
Guidelines section).  In addition, the effects of cryoablation (coagulative necrosis, 
fibrosis, organizing hemorrhage, etc.) will be recorded.  The presence of any remaining 
in situ or invasive carcinoma in the target lesion will be categorized by the pathologist.  
This study will explore possible methods for quantification and development of an 
objective scoring system for any residual cancer after cryoablation for breast cancer.  
Possible methods that may be incorporated or modified include an existing 
classification model for pathologic assessment of tumor response after neoadjuvant 
chemotherapy.  This includes the Symmans method (J Clin Oncol 2007).  
 
7      Follow-up 
7.1        Post-operative Follow-up 
Patients will be seen by the surgical team within 14 days after surgical resection.  
Patients will undergo a physical exam.  No further follow-up after the 14-day post-
surgery visit will be required for this study. 
 
8 
Evaluation of Outcomes 
The rate of complete tumor ablation in the target lesion will be evaluated by pathologic 
review of the surgical specimen.  
The negative predictive value of MRI in the post-ablation setting to determine residual 
in situ or invasive breast carcinoma will be evaluated by radiologic review of pre- and 
post-ablation MRI imaging. 
All patients will be evaluated for adverse events (including pain) associated with 
cryoablation using history and physical examinations. 
The technical variables that may affect success of cryoablation will be reviewed and 
evaluated in procedure notes and on data forms. 
9 
Adverse Event (AE) and Serious Adverse Event (SAE) Reporting 
The prompt reporting of adverse events is the responsibility of each investigator 
engaged in clinical research, as required by Federal Regulations. 
Toxicities/adverse events must be described and graded using the terminology and 
grading categories defined in the most current version of the NCI’s Common Toxicity 
Criteria (CTCAE) version 4.0. The CTCAE is available at 
http://ctep.cancer.gov/reporting/ctc.html.  

 
 
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Attribution to protocol treatment for each adverse event must be determined by the 
investigator and reported on the required forms, using the codes provided. 
 
10 
Routine Adverse Event Reporting 
All expected or unexpected adverse events, regardless of grade or treatment 
attribution, must be recorded on AE case report forms (CRFs).  
 
10.1 Expedited AE and SAE reporting definitions 
The investigator must initially report the AE within 5 calendar days of learning of the 
event.  If death occurs that is unexpected and definitely, probably or possibly related to 
study intervention during and within 30 days after the last day of active study 
intervention, the SAE must be reported within 1 working day (24 hours) from the time 
the research team becomes aware of the event. All SAEs that do not fall under the 
prompt reporting requirements will be reported during continuing review using the 
Internal SAE Log or database printout. 
 
10.2 IRB Policy 
We will follow the University of Texas M.D. Anderson Cancer Center IRB policies and 
procedures in submitting adverse events. 
 
10.3 Expected Adverse Events   
Expected AEs from MRI Contrast  
More Likely 
Less Likely 
Rare but Serious 
Heat sensation 
Hypotension due to 
vasodilatation 
Hypotensive shock  
Dizziness 
Mild allergic reaction 
Anaphylactic reactions 
Nausea 
Local pain and tenderness 
at the injection site 
 
Headache  
 
 
 
Expected AEs from Cryoablation  
More Likely 
Less Likely 
Rare but Serious 
Pain at site of needle 
placement 
Edema at site of treatment 
Hypothermic damage to 
the skin of the breast 
 
Bruising 
Hematoma 
Hematoma requiring 
intervention 
Bleeding at site of needle 
placement 
Bleeding requiring suture 
Bleeding requiring surgical 
intervention 
Infection 
Infection treated with oral 
antibiotics 
Infection requiring IV 
antibiotics 
 
 

 
 
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Expected AEs from Surgical Intervention  
Cosmetic deformity from multiple procedures 
Treatment delays due to complications 
 
11 Statistical Considerations 
 
11.1 Overview of study design 
This is a phase II, one-stage, single arm pilot study to assess the success rate of cryoablation 
therapy following neoadjuvant chemotherapy in the treatment of invasive breast carcinoma.   
11.2 Primary Objective  
The primary objective is to determine the rate of complete ablation.  Complete ablation is 
defined as no remaining invasive or in situ carcinoma present upon pathological examination 
of the targeted lesion.  The rate will be computed as the number of patients with complete 
tumor ablation divided by the total number of eligible patients. 
We will declare that the study is feasible if we observe at least 8 patients with complete ablations 
out of 10 patients.  
11.3 Decision rule 
 
There will be three basic decisions made at the end of this trial: recommend the treatment 
regimen for further trials in selected patient populations, recommend further studies to assess 
whether modifications to the cryoablation technique can achieve the target goal, or 
recommend no further studies of this treatment regimen.  
 
If the number of patients with a complete tumor ablation rate is 8 or more (out of 10 eligible 
patients) we will recommend the treatment regimen for further trials in selected patient 
populations. 
 
If the number of patients with complete tumor ablation is greater than or equal to 5 but less 
than 8 (out of 10 eligible patients), we will recommend testing modifications to the cryoablation 
technique to determine if these will achieve the target goal of 80% success rate or greater. 
 
If the number of patients with a complete tumor ablation rate is less than 5 (out of 10 eligible 
patients), we will recommend no further studies of this treatment regimen. 
 
11.4 Design Characteristics 
The implications of the design depend upon the decision rule and the true (unknown) ablation 
rate. Table 2 characterizes the implications of the proposed decision rule for several different 
true ablation rates. 
 

 
 
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Table 2.  Decision rules 
Decision 
Rule (n=10) 
True 
Ablation 
Rate 
Probability of 
making the 
Decision 
Recommend for 
further trials 
≥ 8 complete 
ablations 
0.50 
0.55 
0.0525 
0.0944 
0.60 
0.1683 
0.65 
0.2696 
0.70 
0.3816 
0.75 
0.5308 
0.80 
0.6722 
0.85 
0.8158 
0.90 
0.9246 
0.95 
0.9885 
Recommend 
testing 
modifications of 
cryoablation 
technique 
≥ 5 and < 8 
complete 
ablations 
0.45 
0.50 
0.4627 
0.5732 
0.55 
0.6419 
0.60 
0.6686 
0.65 
0.6347 
0.70 
0.5705 
0.75 
0.4466 
0.80 
0.3214 
0.85 
0.1829 
0.90 
0.0753 
Recommend no 
further studies 
< 5 complete 
ablations 
0.30 
0.8465 
0.35 
0.7475 
0.40 
0.6303 
0.45 
0.5121 
0.50 
0.3743 
0.55 
0.2637 
0.60 
0.1631 
0.65 
0.0957 
0.70 
0.0479 
 
11.5 Analysis plan 
We will estimate the complete ablation with a 95% confidence interval.   If we observe 8 of these 
patients with complete ablation, then the 95% confidence interval will be 44.4% to 97.5% (Table 
3).    
 
 

 
 
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Table 3. The 95% exact confidence intervals of complete ablation rate if we observed x 
patients with complete ablation out of 10 patients. 
Number of Complete Ablations 
Observed (out of 10) 
Lower Bound of 95% CI 
Upper Bound of 95% CI 
3 
0.0667 
0.653 
4 
0.122 
0.738 
5 
0.187 
0.813 
6 
0.262 
0.878 
7 
0.348 
0.933 
8 
0.444 
0.975 
9 
0.555 
0.997 
10 
0.692 
1.000 
 
12  Protocol Monitoring Plan  
Accrual, adverse event data, and efficacy data will be reviewed by the study team semi-
annually. In addition, efficacy, toxicity, and administrative information for the trial will be 
reviewed by the study team monthly. The study team will monitor the trial for evidence of severe 
adverse events and feasibility and logistical problems.  This includes monitoring for the progress 
of the study, the study and safety of participants, compliance with the consent process and 
assurance of data accuracy and compliance with the protocol. 
 
 
 

 
 
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