ABLATE Registry: Radiofrequency Ablation After Breast
Lumpectomy (eRFA) Added To Extend Intraoperative Margins in the
Treatment of Breast Cancer
Principal Investigator:
V. Suzanne Klimberg, MD
Professor of Surgery and Pathology
Division of Breast Surgical Oncology
University of Arkansas Medical School
Little Rock, AR 72205
KlimbergSuzanne@uams.edu
(501) 686-6504
Co-Principal Investigator:
Dr. Soheila Korourian
Associate Professor of Pathology
Department of Pathology
University of Arkansas Medical School
Little Rock, AR 72205
korouriansoheila@uams.edu
(501) 686-5170
Version 1/05/2010
TABLE OF CONTENTS
I.
Introduction…………………………………………………………………………….3
II.
Study Objectives
III.
IV.
a.
Primary Goals……………………………………………………………….…..…3
b.
Secondary Goals……………………………………………………………………4
Background
a.
Primary RFA of breast cancers…………………………………………………..4
b.
Interim Studies of Intra-Cavitary Radiofrequency Ablation…………...………5
c.
Recent RFA data…………………………………………………………...……....7
Study Design and treatment plan………………………………………………………9
a.
Study Population………………………………….……………………………..…9
b.
Patient Eligibility and Ineligibility………………..………………………………9
i. Patient Selection……………………………………………………..……9
ii. Inclusion Criteria……………………………………………..………….10
iii. Exclusion Criteria………………………………………..………………10
c.
Stratification………………………………………………………..………………10
d.
Study Procedures
i. Visit #1: Clinic……………………………………………………………11
ii. Visit #2: Surgery Day……………………………………………..……..14
iii. Visit #3: Post-Op………………………………………………..………..16
iv. Routine Follow-up Visits……………………………………..…………..17
e.
V.
Possible Toxicities …………………………………………………………...……..18
Data Collection and Monitoring
a. Case Report Forms (CRFs)………………………………………………………….19
b. Site Monitoring ………………………………………………………..…………….19
c. Data Safety Monitoring Board (DSMB)……………………..……………………..19
d. Data Safety Monitoring Plan (DSMP)…………………………….....……………..19
e. Adverse Event Reporting………………………………………………………...….21
f. Quality Control………………………………………………………………………23
VI.
Study endpoints and statistical analyses………………………………………………23
VII.
Confidentiality…………………………………………………………….…………….24
VIII.
References…………………………………………………………………...…………..24
IX.
Appendices
A. Informed Consent Form
B. CRFs
Version 01/05/2010
-2-
I.
INTRODUCTION
Breast Conservation Surgery (BCS) has become an important option and increasingly
preferred choice for women with Stage I or II breast cancer. However, as BCS involves a
compromise between optimal upfront tumor control and cosmesis, rates of re-operation
due to close or positive margins found on the resection specimen are high. Two recent
studies from the Virginia Mason Medical Center in Seattle and the Mt Sinai Hospital in
New York reported the overall rate of re-excision surgery to be, respectively, 30% [1]
and 49% [5]. Besides emotional trauma to the patient, additional operations lead to
increased cost of care, delay in adjuvant treatment and often worse cosmesis.
The purpose of this study will be to evaluate, in a multi-center setting, the ability of
radiofrequency ablation (RFA) of breast cancer lumpectomy sites to extend the “final”
negative margin and consequently decrease the rates of re-operation. During the initial
breast conservation procedure (lumpectomy), immediately following routine surgical
resection of the tumor, radiofrequency energy (RFA) is applied to the wall (bed) of the
fresh lumpectomy cavity, thus extending tumor free margin radially beyond the volume
of the resected specimen. This study will be open at between 25-100 breast cancer clinics
in North America (USA and Canada). Each center will designate a Principal Investigator
responsible for accruing patients to this trial. This study is open to all women that
present to the clinic with operable breast cancer who desire and require breast
conservation surgery (BCS) and fit all of the inclusion criteria and none of the exclusion
criteria. 250 subjects will be selected on a first to qualify, first to register basis.
II.
STUDY OBJECTIVES
Specific Aim: This registry aims to estimate the effectiveness of intra-cavitary
radiofrequency technique (eRFA) in minimizing the re-excision rate and local recurrence
rate in a multi-center setting. [10]
Primary Goals:
1) Estimate the re-excision rate for close (<3mm) or positive margins;
2) Decrease local recurrence;
Version 01/05/2010
-3-
Secondary Goals:
1) Assess cosmesis and quality of life (QOL);
2) Monitor side effects and complications;
3) Monitor the peri-cavitary zone of eRFA-induced Doppler enhancement
4) Monitor treatment related effects on post-operative imaging
III.
BACKGROUND
Primary Radiofrequency Ablation (RFA) of breast cancers
Shortly after its emergence as a tool for unresectable tumors in liver and lung in the 1990ies, radiofrequency was evaluated for its ability to destroy small breast cancers in several
single-center studies [2, 3, 4]. Authors from the M.D. Anderson Cancer Center concluded
that percutaneous radiofrequency ablation of a lesion visualized on ultrasound was
feasible and reproducible, although technical success depended on the accuracy of imageguided probe placement. Patients treated with neo-adjuvant chemotherapy were found to
be poor candidates for ablation, as viable tumor cells undetectable on pre-procedural
imaging may remain peripherally after chemotherapy-induced shrinkage of a larger
primary, compromising accurate image-guided targeting [2]. While a limited numbers of
centers have adopted primary radiofrequency in the treatment of a select subgroup of
women - mostly elderly women with slow-growing, low grade, low risk breast tumors
and/or medical contra-indications to generalized anesthesia [13], its acceptance as a tool
for larger populations has remained limited for primarily the following reasons:
(a)
Following ablation of a primary tumor, the final margin status remains
unknown, depriving the clinician of important prognostic information;
(b)
Since accompanying sentinel node dissection still requires surgery,
there is limited practical benefit gained by treating the primary tumor
with a percutaneous ablation technique;
(c)
Following ablation of a primary tumor, a devitalized mass remains
palpable in the breast for a variable amount of time. For many women,
leaving a palpable mass of unverified viability in place after breast
cancer surgery is psychologically unacceptable;
Version 01/05/2010
-4-
(d)
To allow for tissue banking, permitting future genetic and proteomic
testing essential for drug susceptibility and other uses, resection and
banking of the entire tumor specimen is essential.
Interim Studies of Intra-Cavitary Radiofrequency Ablation: RFA following excision of
the primary tumor
Avoiding the above stated limitations of primary tumor ablation, a different rationale and
method for utilizing radiofrequency ablation in breast surgery was identified and
described by Prof. V. Suzanne Klimberg at the University of Arkansas [10]. She set out
to address the problem of repeated surgeries often required after breast conservation
surgery: 25-49% of US-women require additional re-excision surgery due to close or
positive margins found in the excised specimen [1, 5, 6, 7, 8, 9]. She postulated that
application of radiofrequency generated heat to the lumpectomy cavity wall immediately
after routine surgical excision of the tumor could be a method to extend the “final” intraoperative negative margin and reduce the percentage of women requiring re-excision
surgery, without the adverse outcome on cosmesis associated with upfront wider surgical
excision. Pre-clinical data was obtained using donor mastectomies to assure consistent
ablation margins confirmed by whole mount reconstruction. This data along with her
initial experience with 41 patients and two years median follow-up was recently
published [10]. Out of 41 patients treated with excision and subsequent RFA of the cavity
wall, 25% had inadequate margins in the lumpectomy specimen that was excised prior to
RFA. Only one patient with grossly positive margins was re-excised. At a median followup of two years (range 12-45 months), no patients had experienced a local, in situ
recurrence. Two patients had an elsewhere-in-breast recurrence, both of a different
histologic phenotype than the earlier tumor. The published experience was subsequently
updated to a total of 68 subjects reported at the 2006 San Antonio Breast Cancer
Symposium [11]. Forty-eight had negative margins on the excised specimen, 3 had a 2
mm margin, 9 had a 1 mm margin, 4 were focally positive, and 4 were grossly positive on
final pathology. Only these last 4 had a subsequent mastectomy. Pathological
examination performed on the shaved margins of the cavity after ablation showed no
Version 01/05/2010
-5-
residual cancer in all cases; 64/68 subjects (94%) had no further re-excision or surgery.
No in situ local recurrences were seen at a median follow-up of 17 months.
Variations in both surgical technique and innovations in instrument design were explored
aimed at further standardization of technique, to improve consistency and predictability
of the radial depth of the extended margin, and reduce inter-operator variability. These
studies utilized a vacuum-assisted device (ASSURE™) that uses routine operating room
suction to pull the walls of the resection cavity into the needles of the device. This
obviates the need to apply a “purse-string” suture to pull the cavity walls into the device
prior to ablation. Using the vacuum-assisted technique, in vitro testing was performed at
the Department of Surgery at the University of Arkansas and the Department of
Pathology at West Virginia University, followed in 2006 by clinical in vivo studies in 4
centers in Italy.
Methods
First, an in vitro study was performed at the Department of Pathology at West
Virginia University to establish the performance characteristics of the ASSURE™
vacuum-assisted radiofrequency device in twelve mock lumpectomy cavities that
were prepared in fresh human breast or panniculus tissue. These cavities were
subsequently RFA-treated for 18 minutes. Thermocouples were used to assess the
thermal history across the treatment zone.
Second, an in vivo feasibility study was performed in subjects in Italy previously
scheduled for quadrantectomy with tumors less than 2 cm. This study followed an
“ablate and resect” model: subjects underwent a lumpectomy followed by an in
vivo 15-minute RFA treatment of the cavity walls and subsequent quadrantectomy
that included the RFA-treated region. The RFA-treated cavities were sectioned
fresh in the sagittal and transverse planes to characterize the radius of devitalized
tissue surrounding the cavity. To enhance visualization of the devitalized tissues,
triphenyltetrazolium chloride (TTC) viability staining at 37ºC was performed. As
of March 2007, this study continues to accrue towards a goal of 20 subjects;
preliminary results from the first 6 subjects are reported below.
Version 01/05/2010
-6-
Results
In vitro temperatures in excess of 55ºC for 5 minutes were obtained 3mm from the
probe and exceeded 45 ºC at the treatment region edge. The in vitro and in vivo
anterior/posterior treatment zone heights were 3.9 ± 0.5 cm and 4.5 ± 1.5 cm,
respectively.
Table 1. Minimum TTC-Negative Radii Surrounding the RFA-Treated Lumpectomy Cavity.
Cranial Wall
Cranial / Posterior Wall
Caudal Wall
Caudal / Posterior Wall
Medial Wall
Lateral Wall
Posterior Wall
In Vitro (18mins)
1.3 ± 0.3 cm
1.3 ± 0.3 cm
1.5 ± 0.3 cm
1.5 ± 0.2 cm
1.5 ± 0.5 cm
1.4 ± 0.3 cm
1.3 ± 0.5 cm
In Vivo(15 mins)
1.1 ± 0.5 cm
1.5 ± 0.6 cm
1.3 ± 0.6 cm
1.4 ± 0.7 cm
1.0 ± 0.3 cm
1.0 ± 0.3 cm
1.2 ± 0.3 cm
The interim data supported the feasibility of adjuvant radiofrequency lumpectomy
cavity treatment to extend the mean “final” in situ tissue margins by 1 cm.
Recent RFA data
2009 SSO abstract: Can We Eliminate Radiotherapy after Breast Conservation Therapy?
Results of a Phase II Trial of eRFA. Klimberg VS, Badgwell B, Adkins LL, Smith MA,
Korourian S
Introduction
Margin status is the only prognostic factor that surgeons can affect yet 75 to 90%
of local recurrence (LR) is at the tumor bed even after XRT. We hypothesized
that excision followed by radiofrequency thermal ablation (eRFA) to extend the
margin by 1cm can provide similar therapeutic benefit to XRT. Hence we
proceeded with the current pilot study to determine if creating an additional in
vivo 1cm tumor-free zone around the cavity bed with RFA can decrease LR and
possibly obviate the need for XRT in early breast cancer.
Version 01/05/2010
-7-
Methods
Between 7/02-2/08 we conducted a Phase II trial of RFA in women desiring
lumpectomy. After removal of the cancer with surgical lumpectomy, an RFA
probe was deployed 1 cm circumferentially into the lumpectomy cavity and
maintained at 100◦C for 15 minutes. Intraop doppler was used to follow the
margin ablation. These patients did not receive XRT but did receive systemic
therapy. Patients were followed for local recurrence and cosmesis.
Results
94 pts (mean age:66.68years+11.01SD), 62 invasive, 32 DCIS, tumor size of
1.0cm+0.8cm,S.D. 48 with grade I, 26 with grade II, 19 with grade III, and one
unknown underwent intra-op eRFA. 24 patient had inadequate margins (<2mm)
including 8 grossly positive and four focally positive margins. Eight patients
underwent reresection and were excluded. With a mean follow-up of 23
months+15 months (6-67 months) no LRs in the tumor bed were seen. There were
four elsewhere recurrences – 3 ipsilateral and 1 contralateral. DFS is shown in the
Figure. Two week Cosmesis was scored in 56 patients rating 26 excellent, 22
good, and 8 fair.
Conclusion
Short-term follow-up suggests that in pts with early breast cancer eRFA can
reduce LR without the need for or complications of XRT. eRFA may represent a
new paradigm in achieving optimal breast conservation without XRT. Intraoperative Doppler was reliable in avoiding complications of RFA to skin (i.e.
burns).
This study, as defined in this protocol, aims to validate the initial pre-clinical and clinical
experience reported by Dr. Klimberg in a multi-center setting.
Version 01/05/2010
-8-
IV.
STUDY DESIGN AND TREATMENT PLAN
This multi-center study will evaluate effectiveness of intra-cavitary radiofrequency in
ablating peri-cavitary subcutaneous tissue by assessing short-to-intermediate term
outcomes, including potential adverse events, re-excision rate, cosmesis, indicators of
Quality of Life (Body Image), local recurrence rates, and intra-operative and postoperative imaging. The study, as defined in this protocol comprising 250 subjects, allows
for further technique optimization prior to extending enrollment to larger numbers of
subjects.
4a. Study Population
Subjects will be recruited from participating sites that represent a variety of races,
ethnicities, socioeconomic classes and geographical areas. An initial 250 subjects
will be enrolled in this study.
4b. Patient Eligibility and Ineligibility
Patient selection guidelines
Anticipating that a portion of the patients who participate in this study will
not receive radiation, enrollment will be restricted to patients with a
known low risk of Ipsi-Lateral Breast Recurrence (IBLR):
1. DCIS, age  50, regardless of hormone receptor status;
2. Invasive carcinoma, with all 3 of the following characteristics:
 age  50
 N0 (based on pre-operative assessment)
 Hormone receptor + (ER and/or PR+)
3. Tumors ≤ 3 cm
When a woman presents in clinic, her breast cancer will be evaluated as it
normally would be by a clinical breast exam, review of her imaging
studies and pathology. If she chooses to have breast conservation surgery
Version 01/05/2010
-9-
and meets all of the inclusion criteria and none of the exclusion criteria,
she will be offered the opportunity to participate in the eRFA study.
Inclusion/Eligibility





Patient is a female, ≥ 50 years of age
The tumor size is ≤ 3 cm (on pre-study radiologic OR clinical exam)
The tumor is unicentric and unilateral
The tumor is not involving the skin
Pathology confirms ductal in situ (DCIS) OR infiltrating ductal
carcinoma (IDC), grade I-III
 If tumor is IDC, pathology must be hormone receptor positive (ER+
and/or PR+)
 Patient signs current written informed consent and HIPAA forms
Exclusion/Ineligibility










Patient is under 50 years of age
Patient is male
Tumor > 3 cm in diameter
Bilateral malignancy
Clinically positive lymph nodes
Tumor involving the skin
Pathology confirms invasive lobular carcinoma
Breast implants
Less than 2 years disease-free survival from previous breast cancer
Neoadjuvant chemotherapy or chemotherapy for another breast cancer
within two years
4c. Stratification
Stratification serves to classify subjects in this study into categories with known
differences in rates of ipsi-lateral breast recurrence (ILBR). Since stratification
requires knowledge of the final pathology, and RFA is applied intra-operatively
before final pathology is known, stratification can only be done after enrollment,
i.e. as soon as the final pathology is known. As such, stratification parameters will
not be used as patient selection criteria.
Version 01/05/2010
- 10 -
Subject data will be analyzed for the following characteristics:
(a) nodal status (N0 versus N1 on final pathology)
(b) age ( 50  69 versus 70 and older)
(c) histology (DCIS versus invasive carcinoma)
(d) grade (I versus II versus III)
(e) received adjuvant whole breast radiotherapy (YES versus NO)
(f) patient received adjuvant chemotherapy (YES versus NO)
(g) adjuvant hormonal therapy (YES versus NO)
The sponsor may close patient enrollment to specific risk strata earlier than
enrollment in other risk strata, in order to ensure that adequate numbers of
subjects are enrolled in each risk stratum.
4d. Study Procedures
Visit #1: Clinic
A pre-entry checklist will be completed and signed by a member of the
study personnel, which will confirm the patient’s eligibility. The protocol
will be then be thoroughly explained to the patient and she will be given
the opportunity to ask any pertinent questions. Each member of the study
personnel will be capable and available to answer any questions that the
patient might have.
If she would like to participate in the study, she will be invited to sign
informed consent and HIPAA forms. Copies of the signed pre-entry
checklist and the subject signed consent form will be added to the medical
record. The original paperwork will be placed in the subject’s study chart.
Study personnel at each participating site will then register the subject
with the central database and she will be assigned a sequential study
number.
Version 01/05/2010
- 11 -
After consenting to the study, the subject will fill out her pre-operative
paperwork, and will be assigned to the next mutually convenient operating
day for both she and the surgeon.
The subject will complete two baseline assessments: the Subjective
Cosmetic Scale (BII), as well as the EORTC Body Image
Questionnaire[12], which explores indicators of Quality of Life commonly
affected by breast cancer and/or cancer treatment.
Routine pre-operative evaluations will be done per standard of care for
each institution. An MRI is optional per discretion of the treating surgeon.
Version 01/05/2010
- 12 -
Table 3: Schedule of study-related procedures: specifies the schedule of study related
procedures, to be documented as part of the study records. It is recognized that most
subjects will receive additional care as warranted by their individual circumstances.
Baseline
Surgery
RFA
W2
M6
M12
M18
M
24, 36, 48, 60
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Informed consent
X
Physical Exam
X
Document Cancer Diagnosis
Histologic type
Tumor size
X
X
Tumor receptor status
Tumor location
X
X
Imaging
Mammography
MRI (optional at marked timepoints)
Doppler
Ultrasound*
X
X
X
Pathology
Diagnostic (pre-surgery)
Resection specimen & cavity**
X
X
Intra-operative monitoring
X
Record ablation
Cosmesis & Quality of Life
Patient Assessment
(BII & EORTC)
Physician Assessment
(RTOG Acute Scale)
Physician Assessment
(RTOG Chronic Scale)
X
X
X
Adverse Events/Complications***
X
Adjuvant Therapy
X
* To verify the ablation, Doppler Ultrasound will be used.
** Size, ER/PgR, HER2/neu, BR-grade, pre-ablation resection cavity depth & width.
*** A Case Report Form (CRF) is required ONLY IF an AE and/or Complication is
noted.
Version 01/05/2010
- 13 -
Visit #2: Surgery Day
Once in the operating room, the usual standard procedure for the
institution will be followed for the lumpectomy with the lumpectomy
specimen being sent - without tissue disruption/distortion from the
operating room - to Pathology for routine processing and margin width
assessment. Preparation and resection will be performed as per the routine
of the clinic. After the surgeon has removed the lumpectomy specimen, it
will be taken to Pathology for routine processing.
The excision of the tumor will be immediately followed by the
radiofrequency procedure.
Radiofrequency Ablation (RFA)
System Setup
1. The RF Generator will be programmed and the devices connected
according to the Model 1500X RF Generator User’s Guide. (outlined
below in #2 - #5).
2. The target temperature will be set to 100C.
3. The power will be set to 150 Watts.
4. The generator will be left to Average Temperature mode (default).
5. The timer will be set to 15 minutes for ablating the tissue cavity.
RITA Electrosurgical Device Placement and RF Ablation
1. The investigator will first perform axillary sampling as necessary.
2. The lumpectomy will be performed per the standards of the clinic.
3. Sutures will be placed into the skin and retracted 2 cm away from the
probe to prevent any risk of skin burn from steam.
4. Tissue will be re-approximated to within 1 cm using a purse string
suture.
5. The investigator will insert the RITA Starburst RF-device into the
lumpectomy cavity at the level of the tumor.
Version 01/05/2010
- 14 -
6. The tines of the device will be deployed. The tines of the instrument
may enter the chest musculature but not so deep as the ribs. After
verifying that temperature readings are displayed on the RF Generator,
the RF power will be started using the foot pedal or RF ON/OFF
button. The probe will be deployed 1 cm into the tissue and heated to
100 º C for 15 minutes.
7. Upon completion of the ablation, the “purse string” sutures will be
released.
8. Doppler Ultrasound will be used to monitor the progression of heat
radially into the tissue. Doppler has the ability to record and visualize
the “outgassing” of microbubbles that occurs when tissue is heated by
radiofrequency to 100°C. Projected on a screen, the surgeon can
monitor the radial tissue penetration of heat during the ablation, and
guard against the potential of skin burns, adjusting the needle’s
angulation or location if warranted by the Doppler signal.[14]
Version 01/05/2010
- 15 -
9. After the automatic, 30-second, cool down of the RF probe is
complete, the temperatures will be checked to ensure that the readings
are all above 55C in the tissue If not, RF will be turned on again to
100°C for approximately three more minutes at target temperature.
10. In a large cavity a step-ablation may be required that is one area may
be ablated for 15 minutes. Then the RF probe may be retracted and
repositioned for a second adjoining ablation.
The lumpectomy site will be closed by the surgeon with the standard of
care for lumpectomy procedures. No one other than the surgeon and
his/her immediate team will be involved with the RFA probe or the
ablation process. As performed there should be very little potential for
harm to the subject. If the RFA is deployed too close to the skin the
subject can sustain a skin burn. In initial studies, less than two percent
skin burns have been reported and none using the present technique. Using
the present method the tines of the RFA are visibly deployed and risk of
significant burn is minimized. Risk of infection or disruption of wound
healing has not been increased in our experience with open RFA or in that
of studies using percutaneous RFA. Management of post-operative
complications should require no change in present clinical practice.
An intra-operative case report form (CRF) will be completed for each
subject and placed in the study chart. The margins of the resection
specimen will be evaluated and reported on the pathology CRF. A reexcision of the cavity will be performed according to the criteria below:
Criteria for re-excision after radiofrequency ablation
Re-excision is recommended after radiofrequency ablation
whenever there is gross tumor found at the inked margin of the
resection specimen. Re-excision is not generally recommended for
Version 01/05/2010
- 16 -
close or negative margins (NSABP criteria) after eRFA. In case of
a focally positive margin ( a single <1mm breach of one margin by
either invasive or non-invasive cancer) the final decision regarding
re-excision will be made jointly by the treating site team taking into
consideration the effect of ablation on extending the final surgical
margins and the histology of the tumor.
Visit #3: Post-op
The first post-op visit will occur 1-2 weeks after the study procedure. The
physician will examine the subject and if any complications are present,
these will be recorded in her medical record and the proper CRF will be
completed. Scales to be administered at this visit will include:
(a) The Subjective Cosmetic Result Scale (BII), completed by the patient,
which will help to determine the subject’s feelings about her appearance
after her surgery in comparison to her feelings about her appearance before
surgery.
(b) The RTOG acute scale, completed by the physician, which will record
the difference in the treated breast and skin before and after surgery. This
will also help to determine how successful the procedure is in terms of
cosmetic result.
Routine Follow-Up Visits
The subject will be required to return every 6 months for the first 2 years,
and then yearly (36 months, 48 months, 60 months) until the end of the 5
year study. If the subject chooses to withdraw from the protocol, she may
do so at any time. She will be given the same level of care regardless of
her participation in this study.
Follow-up corresponds closely with the usual follow-up provided to these
subjects under routine clinical practice.
Version 01/05/2010
- 17 -
At each follow-up visit, the physician will examine the subject and if any
complications are present, these will be recorded in her medical record and
the proper CRF will be completed. Scales to be administered at these
visits will include:
(a) The Subjective Cosmetic Result Scale (BII)
(b) EORTC Body Image Scale
(c) The RTOG chronic scale, to be completed by the physician, which will
record long-term effects of the surgery on the affected breast(s).
A unilateral (treated side) mammogram will be performed on all subjects
at 6 and 18 months. Bilateral mammograms will be performed on all
subjects at 12, 24, 36, 48 and 60 months. Results will be recorded on the
Mammogram CRF. An MRI is optional at baseline and any timepoint
thereafter. If done, MRI will be repeated per institutional standard of care
and any abnormal findings will be recorded.
The subject will be treated with adjuvant whole breast radiation, hormonal
therapy or chemotherapy at the discretion of the physician and mutual
decision of the patient. Brachytherapy can be performed but is not
recommended, as it serves the same goal (creating a 1 cm extra margin) as
excision followed radiofrequency ablation. This treatment will be
recorded at the 12 month time point on the Adjuvant Therapy CRF.
4e. Possible Toxicities
Although the exact complication rate is not yet known, adverse toxicity to the
subject is not expected since this procedure is routinely performed in liver,
kidney and breast. It has been shown to be safe and effective. However, if the
RFA is deployed too close to the skin the subject can sustain a skin burn. Less
than five percent skin burns have been reported. Using the present method,
the tines of the RFA are visibly deployed and placed 1 cm into the cavity. The
risk of significant burn is negligible since the heating is at a safe distance from
Version 01/05/2010
- 18 -
the skin. Also, the breast is carefully positioned so that any skin is held away
from the heating at all times during the ablation. Risk of infection or
disruption of wound healing has not been increased in our experience or in
that of studies using by RFA. Management of post-operative burn would
require silvadene for superficial burns and debridement for full thickness
burns. Breast surgery has a five percent chance of infection routinely and
post-operative management is aspiration and antibiotics or open debridement.
V.
DATA COLLECTION AND SAFETY MONITORING
5a. Case Report Forms (CRFs)
Case Report Forms will be used to record demographic, procedural and follow-up
data, as well as any adverse clinical events which may occur. Outside sites will
be required to submit copies of all CRFs to the PI site for central data entry, while
keeping the originals as part of the subject’s study record.
5b. Site Monitoring
Monitoring visits will be made to individual sites only on a limited basis and only
as necessary or as requested by the site team.
5c. Data Safety Monitoring Board (DSMB)
A qualified Data Safety Monitoring Board consisting of a surgeon, a
researcher/epidemiologist, a biostatistician, and a pathologist will be in place.
Their duty will be to monitor data gained from these research activities to assure
the continuing safety of research participants, relevance of the study questions,
appropriateness of the study and integrity of the accumulating data.
5d. Data Safety Monitoring Plan (DSMP)
The PI will be responsible for reviewing interim analysis of data prepared by the
study statistician and for recommending whether the study needs to be changed or
terminated based on these analyses. The PI will also determine when the results
Version 01/05/2010
- 19 -
of the study should be published or otherwise released to the public. The IRB will
also review any major modifications to the study proposed by the PI. Unplanned
monitoring of a given study may be requested by the sponsors, any member of the
study team, IRB, or the DSMB. A written report outlining the current status of
the trial will be developed by the study statistician after Phase I is completed. The
report may contain recommendations on whether to close the study, whether to
report the results, whether to continue accrual or follow-up, and whether an IRB
or PRMC or DSMB discussion is needed. Unless the DSMB requests a DSMB
discussion, the recommendations will be accepted without discussion. When a
DSMB discussion is necessary, the DSMB will develop its recommendations. The
DSMB will provide recommendations to the PI, the IRB and the study sponsor,
along with copies of the written reports prepared by the study statistician. In the
event that a change in a trial is recommended for patient safety reasons, including
early stopping, the PI will act to implement the change as rapidly as possible. The
PI is responsible for communicating these recommendations to the UAMS IRB
and the study sponsors in a timely manner. If a change in the trial is
recommended for reasons other than patient safety, the PI will be responsible for
communicating the recommendation and the rationale to the UAMS IRB (and any
objections) whose approval will be required prior to implementation.
The PI DSMB and the study statistician will be the only individuals with regular
access to the primary data during the accrual phase, although toxicity and accrual
information will be presented to the study team of investigators on a regular basis.
Release of data to a small, specified group of investigators for planning purposes
is acceptable after the last patient has completed treatment, or otherwise as
determined to be necessary by the DSMB.
Additional monitoring of the progress of clinical trials is provided on a regular
basis by a weekly Breast Cancer Conference held every Wednesday at 7 am at
the PI site. This is attended regularly by a multidisciplinary team of physicians,
nurses, biostatisticians, clinical research associates (CRAs), and data management
Version 01/05/2010
- 20 -
personnel. Attendance and minutes are kept at each meeting, with actions and
recommendations generated and responded to regularly. At each meeting, the
following elements of breast cancer clinical trials are reviewed and action taken, if
applicable:
 Accrual
 Patient flow through each stage of the protocol to review patient compliance
with treatment
 Serious adverse event
 Deaths
 Patients removed from protocol treatment and reasons why
 Any deviations from eligibility or protocol-specified treatment
A third method of monitoring the clinical trial is the generation of regular reports
to the PI by the biostatisticians and data management groups. The patient flow
diagram will be updated on a monthly basis and patients that are found to be noncompliant for any reason will be investigated and properly documented. The
following information will be reported to the IRB and treating investigators:
 Adverse events experienced - Any serious adverse events experienced
(including hospitalizations, grade 4-5 toxicity, or any unexpected reactions).
will be reported immediately as described in the next section.
Morbidity and mortality are monitored on a monthly basis to determine if deaths
are related to disease, toxicity, or other risk factors to determine if these rates are
within the expected range.
5e. Adverse Event Reporting
All adverse events (AEs) will be captured by patient interviews at each clinic visit
by study staff. All AEs, whether felt to be related to study treatment or not, will
be recorded in the appropriate section of the case report form. The report will
include, whenever possible, the investigator's written medical judgment as to the
Version 01/05/2010
- 21 -
relationship of the adverse experience to study treatment(s) (i.e., “probable,”
“possible," or "unrelated").
Serious Adverse Events (SAEs)
If an AE is determined to be serious, a separate SAE CRF will be completed.
SAE reporting is performed according to FDA guidelines and the NCI common
toxicity criteria. An AE will be classified as serious if:
1. It resulted in death (i.e., the encountered AE caused or led to death); or
2. It was immediately life threatening (i.e., the encountered AE placed the patient
at immediate risk of death; it does not apply to an AE which hypothetically might
have caused death if it were more severe); and/or
3. It required or prolonged in-patient hospitalization (i.e., the encountered AE
required at least a 24-hour in-patient hospitalization or prolonged a hospitalization
beyond the expected length of stay; hospitalizations for elective medical/surgical
procedures, scheduled treatments, or routine check ups are not an AE by this
criterion); and/or
4. It was disabling (i.e., the encountered AE resulted in a substantial disruption of
the patient's ability to carry out normal life functions); or
It resulted in a congenital anomaly/birth; or
It does not meet any of the above serious criteria but may jeopardize the patient
and require medical or surgical intervention to prevent one of the outcomes listed
above; or
It is an unexpected event.
SAEs will be reported to the PI by telephone or fax as soon as possible, but in all
cases within 10 business days of learning of the event. The PI is required to
notify the Institutional Review Board (IRB) as soon as possible as follows: within
7 days of observing or learning of a serious and/or unexpected adverse event;
otherwise, within 60 days of investigator’s notification of the death; immediately
for any protocol deviation or violation if it represents a significant alteration in the
approved protocol and/or if it affects the safety or welfare of the subject; prompt
Version 01/05/2010
- 22 -
notification within 30 days for changes in approved research procedures or
protocol (amendments); immediately upon discovery of noncompliance; within 3
days of restrictions, suspensions, or termination of study by the sponsor or
principal investigator; within 7 days of activity which involves a potential or
actual unanticipated risk to subjects or others. Otherwise, reports will be given
during continuing review.
5f. Quality Control
The first five cases from each institution will monitored by the Principal
Investigator (Klimberg) via Sharepoint. If the participating physician proves
adept at monitoring the eRFA procedure with Doppler he/she will be given
permission to continuing accruing patients to the study. If he/she is unable to do
so, the site investigator will come to the PI institution for re-training and be remonitored. If the investigator still is unable to properly monitor the procedure,
the investigator will not be allowed to accrue further patients.
VI.
STUDY ENDPOINTS AND STATISTICAL ANALYSES
Statistical Considerations
Previous reports show that 25% of patients have inadequate margins after excision and
prior to RFA [10]. A sample size of 250 patients will be sufficient to detect a reduction
in the proportion of patients with inadequate margins requiring re-excision with RFA to
12.5% at the two-sided 0.05 significance level with power of 0.99. The re-excision rate
can be estimated with a 95% confidence interval of width no greater than + 4%.
The binomial proportion and its 95% confidence interval will be used to estimate the
proportion with inadequate margins following RFA. The adequacy of the margins will be
determined after excision and before RFA, and after RFA, and McNemar’s test will be
used to determine compare the proportion of patients with inadequate margins before and
after RFA.
Version 01/05/2010
- 23 -
The Kaplan-Meier method will be used to evaluate time to recurrence. The cumulative
proportion of recurrences at one year and two years will be estimated using the 95%
confidence intervals.
Adverse event data will be tabulated by adverse event category, severity and relationship
to RFA. The incidence of adverse events will be estimated using the binomial proportion
and its 95% confidence interval.
VII.
CONFIDENTIALITY
Any information obtained in this study will be kept confidential and anonymous. If the
results of this study are published in medical literature, participant’s names will not be
identified. Study results will be published in aggregate, based on data entered on the case
report forms and in the central study database. Individual Centers will not endeavor to
publish single-center data.
VIII. REFERENCES
1) Peterson DJ, Wechter DG, Jacobs TW. Rate of re-excision with breast-conserving
surgery in stage I and II breast cancer patients: a retrospective study. Breast
Cancer Research and Treatment 2006; 100 (S1):S122, Abstract 2125.
2) Fornage BD. Sneigne N, Ross AI, Mizra AN, Kuerer HM, Singletary SE. Small
(≤2 cm) Breast Cancer Treated with US-guided Radiofrequency Ablation:
Feasibility Study. Radiology 2004;231:215-224.
3) Singletary SE, Fornage BD, Sneigne N et al. Radiofrequency ablation of earlystage invasive breast tumors: an overview. Cancer 2002; 8:177-180.
4) Noguchi M, Earashi M, Fujii H et al. Radiofrequency Ablation of small breast
cancer followed by surgical resection. Journal of Surgical Oncology
2006;93:120-128
5) Menes TS, Tartter PI, Bleiweiss I, Godbold JH, Estabrook A, Rosenbaum Smith
S. The Consequence of Multiple Re-Excisions to Obtain Clear Lumpectomy
Margins in Breast Cancer Patients. Ann Surg Oncol 12:881-885, 2005
6) Fleming FJ, Hill AD, McDermott EW, et al: Intra-operative margin assessment and reexcision rate in breast conserving surgery. European Journal of Surgical Oncology
30:233-7, 2004.
7) Leong C, Boyages J, Jayasinghe UW, et al: Effects of margins on ipsilateral breast
tumor recurrence after breast conservation therapy for lymph node-negative breast
carcinoma. Cancer 100:1823-32, 2004
Version 01/05/2010
- 24 -
8) Meric F, Mirza NQ, Vlastos G, et al: Positive surgical margins and ipsilateral breast
tumor recurrence predict disease-specific survival after breast conserving therapy.
Cancer 97:926-933, 2003
9) Singletary SE: Surgical margins in patients with early-stage breast cancer treated with
breast conservation therapy. Am J or Surg 184:383-93, 2002
10) Klimberg VS, Kepple J, Shafirstein G, Adkins L, Henry-Tillman R, Youssef E et
al. eRFA: Excision followed by RFA - a New Technique to Improve Local
Control in Breast Cancer. Annals of Surgical Oncology 2006; 13:1422-1433.
11) Klimberg VS, Korourian S, Henry-Tillman RS, Margulies AG, Adkins L,
Mumford S, Shafirstein G, Ferguson S. Obtaining negative margins after
lumpectomy with eRFA prevents re-operation. Breast Cancer Research and
Treatment 2006; 100(S1): S289, Abstract 6100.
12) Hopwood P, Fletcher I. Lee, A, Al Ghazal S. A body image scale for use with
cancer patients. European Journal of Cancer 2001 ;37 :198-197.
13) Susuni T, Nori J, Oliveiri S, Livi L, Bianchi S, Mangialavori G, Branconi F,
Scarcelli G. Radiofrequency ablation for minimally invasive breast carcinoma : A
Pilot study in elderly inoperable patients. Gynecologic Oncology 2007; 104 :304310.
14) Bland KL, Gass J, Klimberg VS. Radiofrequency, Cryoablation and other
modalities for breast cancer ablation. Surgical Clinics of North America 2007;
87:539-550.
IX. APPENDICES
A. Informed consent form: The informed consent form will be formatted per
local requirements from the IRB of each participating center. A template
consent form, as used for this program at the University of Arkansas, has been
provided to each center.
B. Add all CRFs
Version 01/05/2010
- 25 -