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 ArkansasMedicalSchool

Little Rock, AR72205

(501) 686-6504

Co-Principal Investigator:

Dr. Soheila Korourian

Associate Professor of Pathology

Department of Pathology

University of ArkansasMedicalSchool

Little Rock, AR72205

(501) 686-5170

Version 1/05/2010

TABLE OF CONTENTS

  1. Introduction…………………………………………………………………………….3
  2. Study Objectives
  3. Primary Goals……………………………………………………………….…..…3
  4. Secondary Goals……………………………………………………………………4
  5. Background
  6. Primary RFA of breast cancers…………………………………………………..4
  7. Interim Studies of Intra-Cavitary Radiofrequency Ablation…………...………5
  8. Recent RFA data…………………………………………………………...……....7
  9. Study Design and treatment plan………………………………………………………9
  10. Study Population………………………………….……………………………..…9
  11. Patient Eligibility and Ineligibility………………..………………………………9
  12. Patient Selection……………………………………………………..……9
  13. Inclusion Criteria……………………………………………..………….10
  14. Exclusion Criteria………………………………………..………………10
  15. Stratification………………………………………………………..………………10
  16. Study Procedures
  17. Visit #1: Clinic……………………………………………………………11
  18. Visit #2: Surgery Day……………………………………………..……..14
  19. Visit #3: Post-Op………………………………………………..………..16
  20. Routine Follow-up Visits……………………………………..…………..17
  21. Possible Toxicities…………………………………………………………...……..18
  22. 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

  1. Study endpoints and statistical analyses………………………………………………23
  2. Confidentiality…………………………………………………………….…………….24
  3. References…………………………………………………………………...…………..24
  4. Appendices

A. Informed Consent Form

B. CRFs

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 VirginiaMasonMedicalCenter 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. 250subjectswill 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;

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 1990-ies, radiofrequency was evaluated for its ability to destroy small breast cancers in several single-center studies [2, 3, 4]. Authors from the M.D.AndersonCancerCenter concluded that percutaneous radiofrequency ablation of a lesion visualized on ultrasound was feasible and reproducible, although technical success depended on the accuracy of image-guided 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;

(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” intra-operative 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 follow-up 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 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 VirginiaUniversity, 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 VirginiaUniversity 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.

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.

In Vitro (18mins)In Vivo(15 mins)

Cranial Wall1.3 ± 0.3 cm1.1 ± 0.5 cm

Cranial / Posterior Wall1.3 ± 0.3 cm1.5 ± 0.6 cm

Caudal Wall1.5 ± 0.3 cm1.3 ± 0.6 cm

Caudal / Posterior Wall1.5 ± 0.2 cm1.4 ± 0.7 cm

Medial Wall1.5 ± 0.5 cm1.0 ± 0.3 cm

Lateral Wall1.4 ± 0.3 cm1.0 ± 0.3 cm

Posterior Wall1.3 ± 0.5 cm1.2 ± 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.

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. Intra-operative Doppler was reliable in avoiding complications of RFA to skin (i.e. burns).

This study, as defined in this protocol, aims to validate the initialpre-clinical and clinical experience reported by Dr. Klimberg in a multi-center setting.

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 post-operative imaging. The study, as defined in this protocol comprising 250subjects, 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 250subjects 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 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.

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.

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.

Baseline / Surgery
RFA / W2 / M6 / M12 / M18 / M
24, 36, 48, 60
Informed consent
X
Physical Exam
X / X / X / X / X / X
Document Cancer Diagnosis
Histologic type / X
Tumor size / X
Tumor receptor status
/ X
Tumor location
/ X
Imaging

Mammography

/ X / X / X / X / X

MRI (optional at marked timepoints)

/ X / X / X / X / X

Doppler

Ultrasound*

/ X
Pathology
Diagnostic (pre-surgery)
/ x
Resection specimen & cavity**
/ x
Intra-operative monitoring
Record ablation
/ X
Cosmesis & Quality of Life

Patient Assessment

(BII & EORTC)

/ X / X / X / X / X / X
Physician Assessment
(RTOG Acute Scale)
/ X
Physician Assessment
(RTOG Chronic Scale)
/ X / X / X / X
Adverse Events/Complications***
X / X / X / X / X
Adjuvant Therapy
X

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.

* To verify the ablation, Doppler Ultrasoundwill be used.