Annals of Surgical Oncology Cite Track
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
10.1245/s10434-006-9151-4
Annals of Surgical Oncology 13:1422-1433 (2006)
© 2006 Society of Surgical Oncology
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Klimberg, V. S.
Right arrow Articles by Korourian, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Klimberg, V. S.
Right arrow Articles by Korourian, S.

Original Article

eRFA: Excision Followed by RFA—a New Technique to Improve Local Control in Breast Cancer

V. Suzanne Klimberg, MD1,2, Julie Kepple, MD1, Gal Shafirstein, PhD3, Laura Adkins, MAP1, Ronda Henry-Tillman, MD1, Emad Youssef, MD4, Jorge Brito, MD5, Lori Talley, BS2 and Soheila Korourian, MD2

1 Department of Surgery, Division of Breast Surgical Oncology, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 725, Little Rock, AR 72205, USA
2 Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA
3 Department of Otolaryngology, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA
4 Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock AR 72205, USA
5 Department of Radiology, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA

Correspondence: Address correspondence and reprint requests to: V. Suzanne Klimberg, MD; Department of Surgery, Division of Breast Surgical Oncology, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 725, Little Rock, AR 72205, USA; E-mail: klimbergsuzanne{at}uams.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Introduction: Excision followed by RFA (eRFA) may allow improved cosmesis while ensuring negative margins in patients with breast cancer. This technique utilizes heat to create an additional tumor-free zone around the lumpectomy cavity. We hypothesized that eRFA will decrease the need for re-excision of inadequate margins.

Methods: Between July 2002 and January 2005, we conducted a multiphase trial of RFA of prophylactic mastectomy specimens and of women desiring lumpectomy. In both models, a lumpectomy was performed, the RFA probe was deployed 1 cm circumferentially into the walls of the lumpectomy cavity and maintained at 100°C for 15 min. Whole mount slides were used to measure the zone of ablation for ex vivo specimens. Hematoxylin and eosin staining of in vivo lumpectomy margins <3 mm was considered inadequate.

Results: Nineteen prophylactic mastectomy ablations revealed a consistent perimeter of ablation. Forty-one patients (mean age 63 ± 14 years) had an average tumor size of 1.6 ± 1.5 cm underwent in vivo eRFA, and 25% had inadequate margins: one focally positive, one <2 mm, eight <1 mm and one grossly positive. Only the grossly positive margin was re-excised. Overall complication rate of in vivo ablations was 7.5%. Twenty-four of 41 patients did not have post-eRFA XRT. No in-site local recurrences have occurred during a median follow-up of 24 months (12–45 months). Two patients have occurred elsewhere.

Conclusions: The ex vivo ablation model reliably created a 5–10 mm perimeter of ablation. In vivo, this zone reduced the need for re-excision for inadequate margins by 91% (10/11). Short-term follow-up suggests that eRFA could reduce re-excision surgery and local recurrence.

Key Words: eRFA • Breast cancer • Lumpectomy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The primary purpose of breast-conservation surgery (BCS) is to remove the tumor and obtain negative margins (a tumor-free zone) around the lumpectomy cavity to minimize the chance of local in-breast tumor recurrence.1–4 Breast irradiation is added to further "sterilize" the lumpectomy site.2,5–12 Despite this, inadequate margins are found at the first operation in 20–55% of breast cancers removed by open lumpectomy. In addition, 75–90% of recurrences occur at the site of the original lumpec-tomy.5,11,12 This predictability of the site of recurrence highlights the inadequacy of both intra-operative and permanent pathologic evaluations. Routine pathology samples are inadequate in comparison with the overall size of the margin, with little more than 1/1,000 of the margin edge examined.13 Because closer margins increase the recurrence rate, a 3-mm margin is an important metric to potentially avoid a recurrence.14 Yet, even when adequate negative margins are achieved, reexcision reveals residual disease in more than 25% of cases.14,15

Although a secondary purpose of current BCS is to achieve better cosmesis, the treatment itself often results in deformity at the lumpectomy site. One reason for deformity is the large volume of tissue removed to obtain negative margins, particularly with repeat reexcision.16

Partial or local breast radiation therapy (XRT), now considered a viable alternative to whole-breast XRT, gives a full XRT dose only to the 1 cm of tissue around the perimeter of the cavity site. Five-year follow-up of multiple small series of partial-breast irradiation (PBI) shows no differences in local recurrence rate (LRR) from whole-breast XRT, leading some to accept PBI as therapeutically equal to whole-breast XRT.17–19 Based on this historical perspective and on our preliminary preclinical and clinical data, we purport that our newly developed technique, eRFA of the lumpectomy cavity provides the best opportunity to ensure intraoperatively negative margins in patients with breast cancer while improving cosmesis (Fig. 1Go). RFA of the lumpectomy cavity perimeter uses heat to create a wider tumor-free zone or margin around the lumpectomy cavity following optimal tumor resection without further tissue removal at the time of the original operation. We expect further follow-up to confirm that eRFA decreases LRR because most LRs are in the tumor bed.5,11,12


Figure 1
View larger version (28K):
[in this window]
[in a new window]

  		FIG. 1. Excision followed by radiofrequency ablation (eRFA) concept. Open excision followed by RFA ablates an extra centimeter of tissue around the periphery of the cavity to treat residual disease without addition tissue removal.

 
We hypothesize that eRFA will ensure negative margins at the time of the first operation in patients with breast cancer, preventing reresection, improving cosmesis, and possibly improving LRR. Our overall research goal is to reduce the LRR of breast cancer by establishing a novel treatment paradigm that makes use of a combination of standard and cutting-edge technologies.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Two groups of patients are reported here under institutional review board (IRB)-approved protocols from July 2002 to January 2005. Group I was a group of patients undergoing mastectomy for any reason who consented to let their removed breast be used for performing a simulated lumpectomy followed by RFA. Group II was a group of patients undergoing lumpectomy in which RFA was used as a means to achieve negative margins at the first operation.

Mastectomy-Donor-Simulated Lumpectomy
Simulated lumpectomies of 1x1 cm were performed in fresh ex vivo mastectomy specimens (group I) followed by RFA (100°C for 15 min) of the resection bed perimeter. Figure 2Go demonstrates the simulated lumpectomy, deployment of the RF probe to 2 cm (greatest diameter of the probe), the ablation zone, and the measurements taken. The cavity and ablation zone were then resected and underwent pathologic whole-mount reconstruction.


Figure 2
View larger version (8K):
[in this window]
[in a new window]

  		FIG. 2. Ex-vivo-simulated lumpectomy and radiofrequency ablation (RFA). Double-headed arrows demonstrate measurements taken.

 
Patients Undergoing eRFA
Preoperative Examination
Group II patients were evaluated according to standard care, which includes a clinical breast exam and a review of their imaging studies and pathology results.

Lumpectomy Surgery and RFA Procedure (eRFA)
Group II subjects participating in this trial had a standard lumpectomy procedure under general anesthesia. All injections for sentinel lymph node (SLN) or otherwise were away from the primary tumor site because such injections could potentially affect the RFA treatment. After the surgeon removed the lumpectomy specimen, it was promptly submitted to the pathology laboratory for routine processing. Immediately following the lumpectomy, the subject underwent eRFA using the RITA Medical Systems Starburst XL RFA probe (RITA Medical Systems, Mountain View, CA, USA). RFA is currently approved by the Federal Drug Administration (FDA) for ablation of subcutaneous tissue. eRFA follows standard tumor removal, creating an additional tumor-free zone of breast subcutaneous tissue by ablation instead of further surgical removal (Fig. 3Go) One or more absorbable pursestring sutures were used to reduce the lumpectomy cavity to less than 2 cm. Sutures were placed into the skin and retracted 2 cm away from the probe to prevent skin burn. The RFA probe was then deployed around the perimeter of the cavity to a depth of 1 cm into the tissue and heated to 100°C for 15 min.


Figure 3
View larger version (105K):
[in this window]
[in a new window]

  		FIG. 3. Excision followed by radiofrequency ablation (eRFA). Excision followed by open ablation. After lumpectomy, the tines of the RFA probe are visually inserted for 1 cm circumferentially into the cavitary walls.

 
In RFA, frictional heat generated by intracellular ions moving in response to an alternating high-frequency current results in tissue coagulation, causing cell death and the destruction of solid tumors. An RFA probe, consisting of a tube with retractable prongs, is positioned and monitored under ultrasound (US) guidance. RFA was performed in temperature mode. Increasing the area of current conduction can effect an ablation zone of 3–7 cm in diameter in a variety of tissues.20–27

At the end of the 15-min exposure, the RF energy was turned off, and the temperature of tissue at the tip of the probe was monitored for 30 s. If tissue temperature fell to <55°C in 30 s, the RF energy was turned on for an additional 3 min, after which the RF energy was again turned off. After a cool-down period of approximately 1 min, the pursestring suture was released, the probe retracted, and the device removed from the lumpectomy cavity.

Initial Post-operative Exam
In group II patients, the objective status of the subject’s breast healing and any findings were noted during the clinical examination, such as bruising, burns, and skin changes. The decision about treatment with adjuvant therapy was recorded to document the subject’s postsurgery treatment plan.

Evaluation for Recurrence
Patients’ breast cancer recurrence was evaluated by history of symptoms, changes in physical exam, and/or standard mammograms. Patients were evaluated for significant change in physical exam, increased area of scar, or suspicious calcifications. Mammography was performed for each subject at the 6-month examination. Patients continue to be followed yearly for life and examined annually to monitor general health status and distant relapse, as is usual standard of practice.

Pathology
Whole-Mount Reconstruction of Simulated Lumpectomy from Mastectomy Donors
The cavity and ablation zone were resected and underwent pathologic whole-mount reconstruction using hematoxylin and eosin (H&E) staining. Proliferating cell nuclear antigen (PCNA) staining was used to confirm nonviability within ablation zones microscopically identified.28,29 Areas of positive staining were assessed using the PCNA antibody (Biomeda Corp.), together with digital image analysis. PCNA staining was used to determine actively replicating DNA; absence of PCNA staining serves as a surrogate for cell death to assess the ablation zone depth.29 Computer modeling was used to create three-dimensional (3D) reconstructions of the cavity and the ablated margins using ultra-high-resolution scanning of 3-mm sections on sequential microscope slides. A true occurence versus recurrence was designated as a distinctly different mass and in a distintively different location from the primary cavity.30

Standard Lumpectomy Specimens
Initially, all specimens were sent to the institution’s pathology laboratory for H&E staining and evaluation to provide timely feedback for treatment. Specimens were weighed and measured and the surgical margins inked. The margins of each lumpectomy specimen were evaluated for the presence of any residual disease.

Data Analysis and Statistical Methods
During the study, patients were monitored for recurrence every 6–12 months. Magnetic resonance imaging (MRI) was used only if there was a suspicion of recurrence. In the presence of RFA, we expect the 2-year LRR to be ~5%, consistent with the experience of patients with brachytherapy.17–19 Lim et al. in a group of 81 patients with T1 low-grade lesion excised with wide margins had a 23% LRR with 86-month follow-up without XRT but with hormonal therapy.31 Eight-year follow-up of National Surgical Adjuvant Breast and Bowel Project (NSABP) B–21, a randomized trial of ≤ 1-cm cancers, found ipsilateral breast tumor recurrence to be 16.5% with tamoxifen alone versus 9.3% with XRT alone versus 2.8% with tamoxifen and XRT.32 The patients here were not selected for small or even favorable lesions and represent a very homogenous group, as seem in clinical practice. This preliminary study did not have the power to detect difference or not from historic controls for LRR given XRT but was directed at providing proof of concept and making data available for power calculations. A 2-year LRR of > 10% in patients receiving systemic therapy but not XRT would have required all patients to receive XRT.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Ex-Vivo-Simulated Ablate-and-Resect Protocol in Mastectomy Specimens
To prove the capability of RFA to ablate the perimeter of a cavity, we obtained preclinical data in a simulated ablate-and-resect protocol using fresh ex vivo mastectomy specimens. Nineteen simulated lumpectomies were followed by RFA (100°C for 15 min) of the perimeter of the resection bed. Figure 2Go demonstrates the simulated lumpectomy, RF probe deployment, the ablation zone, and the measurements taken. The cavity and ablation zone were then resected and underwent pathologic whole-mount examination (Fig. 4Go). Figure 5Go shows the average radially ablated margin measurements around the simulated lumpectomy cavity and demonstrates consistent radial ablation. In addition to the margin measured, ablation did cause unquantifiable liquefaction of fat in the lumpectomy cavity. PCNA staining confirmed 100% nonviable tissue within the ablation zones.


Figure 4
View larger version (119K):
[in this window]
[in a new window]

  		FIG. 4. Whole-mount, with circle depicting zone of ablation created by radiofrequency ablation (RFA) around the simulated lumpectomy site.

 

Figure 5
View larger version (24K):
[in this window]
[in a new window]

  		FIG. 5. Average radial ablated margin measurements around lumpectomy cavity.

 
For each of 19 specimens, we used computer modeling to create 3D reconstruction of the cavity and ablated margins (Fig. 6aGo). We also modeled the ablated regions from ultra-high-resolution scanning of 3-mm sections on sequential microscope slides (Fig. 6b). The ablation zones created were more cylindrical than the anticipated spherical shape.


Figure 6
View larger version (47K):
[in this window]
[in a new window]

  		FIG. 6. A,B. Three-dimensional (3D) reconstruction of mastectomy specimens. A Nine layers, each 3-mm thick, from pathologic whole-mount reconstruction were used for computer modeling. The green volume represents the cavity; the blue frame represents the margins. B Reconstruction performed from microscope slides scanned at ultrahigh resolution. The red object represents the ablated region; the blue planes each represent the location of a slide. Slides were 3 mm apart.

 
Patients
From July 2002 through January 2005, 41 patients underwent intraoperative eRFA. Mean patient age was 63 years [±14 standard deviation (SD)] (range 37–89); tumor size averaged 1.6 cm (±1.5 SD) (range 0.1–4 cm). Nine were ductal carcinoma in situ, four invasive lobular, one adenoid cystic, and 27 invasive ductal carcinoma (four mucinous, two tubulolobular, one mixed type, and 19 not otherwise specified). There were nine Tis, four T1a, eleven T1b, ten T1c, four T2, and three T3 (with a good response after chemotherapy). There were 18 grade I, 11 grade II, and 12 grade III patients. Seventeen patients had post-eRFA XRT, five of whom had neoadjuvant chemotherapy to shrink the tumor prior to lumpectomy. Twenty-four patients did not have post-eRFA XRT. Two patients had pre-eRFA XRT: one for Hodgkin’s disease and the other for breast cancer. The patient with previous breast cancer had a 3-mm invasive ductal carcinoma and refused mastectomy.

Pathology
eRFA was performed in group II patients in order to assure negative margins at the time of surgery. (Fig. 7Go). Patients with intraoperatively positive (IOP) margins underwent immediate resection. Of those with negative IOP margins by touch-prep cytology, one patient was grossly positive for lobular carcinoma and underwent mastectomy. This patient’s eRFA showed a 1-cm ablation of tumor around the cavity edge. Ten patients had close or positive margins on final report: eight had 1-mm margins, one had 2-mm margins, and one was focally positive. None of these patients were reresected. In the group of remaining patients with negative (≥ 3-mm) margins, studies estimate that 25% (approximately eighnt) will have occult positive margins on reresection.14,15 Taken together, it can be estimated that ~45% of these patients should benefit from this added intra-operative procedure. Six patients were node positive. MRI (Fig. 8Go) and pathology (Fig. 9Go) of the two patients with elsewhere recurrences revealed no residual disease at the cavity site on H&E and no residual ablated tissue at the ablated cavity edge.


Figure 7
View larger version (16K):
[in this window]
[in a new window]

  		FIG. 7. Impact of radiofrequency-ablation (RFA)-assisted lump-ectomy on lumpectomy margins. Potential impact of RFA is seen in 45% of all patients including 9* who had closer or + margins in 8** patients with occult + margins.

 

Figure 8
View larger version (99K):
[in this window]
[in a new window]

  		FIG. 8. A–C Imaging of excision followed by radiofrequency ablation (eRFA). A Mammo-gram 6 months after eRFA. B Postcontrast magnetic resonance imaging (MRI) of eRFA site at 1 year. Gray arrow demonstrates fine rim around previous lumpectomy cavity, with no signs of residual disease or ablation zone. Black arrow shows normal glandular tissue that enhances on both pre- and postcontrast films. MRI scan. C Positron emission tomography computed tomography (PET-CT) of eRFA site at 1 year. RFA-C 2- and 5-h trans and coronal PET-CT demonstrating a 3-mm rim of ablation.

 

Figure 9
View larger version (121K):
[in this window]
[in a new window]

  		FIG. 9. Hematoxylin and eosin (H&E) of excision followed by radiofrequency ablation (eRFA) cavity at 1 year in a patient with elsewhere recurrence in the breast showing only a few mm of residual ablated tissue.

 
LRR and Follow-Up after eRFA
On final pathology, 25% of the patients had inadequate margins (<3 mm) and would otherwise require reexcision to reduce LRR. One patient with lobular cancer and grossly positive margins underwent mastectomy. Twenty-four node-negative patients did not receive XRT. After a median follow-up of 24 (range, 12–45) months, no in-site LRs (none less than 5 cm from cavity site) have been seen. Since most LRs should occur during the first 2 years, this compares very favorably with that of other series and appears to be safe.30,31 Caveats are that this group of patients is much more diverse in size and treatment. With the small group of patients, no statistical conclusions can be made. There have been two elsewhere recurrences in a breast. The first was 8 cm away from the primary tumor bed in a different quadrant of the breast and was an invasive lobular tumor compared with primary DCIS. This occurred at 1 year. The other was 5 cm away from the primary and was an 8-mm, grade II invasive carcinoma compared with the grade III primary tumor. This occurred at 2.3 years of follow-up. Both patients underwent successful salvage mastectomy. No patient in this study had developed systemic disease at the time of this report.

Imaging
In addition to the need for better techniques to treat breast cancers and margins, a technique for assessing the ablation zone is also needed. We evaluated currently available imaging methods with the purpose of determining the best method for assessing the success of margin ablation. We assessed several standard techniques, including mammography at 6-month intervals following eRFA and MRI and positron emission tomography (PET)-CT when indicated (Fig. 8Go). We found that the area of ablation ranged from not visible to minimally visible on mammography a majority of the time. When visible, it appeared as a ring of fat necrosis at the ablation site. At first, we thought that MRI and PET resolution may be too low to be useful in determining margin width. However, using time sequencing, we think that MRI and PET-CT can determine inflammation at the eRFA site versus recurrence. From studying the cavity sites (Fig. 9Go) of the two patients who underwent resection after eRFA for elsewhere recurrences, we believe that the ablated tissue is—for the most part—reabsorbed and therefore will be undetectable on most imaging modalities.

Complications
The postoperative complication rate in these patients was 7.5% (3/41). This included one significant burn that was treated conservatively in the clinic and healed with retraction of the skin over the burned area. The second was a minor burn at the skin edge (<5 mm) that healed without sequelae. The third occurred in a diabetic patient in chronic renal failure (CRF) and congestive heart failure (CHF) who had wound healing delay with subsequent wound infection. The patient’s wound healed, but she died 4 months postoperatively secondary to CHF. There were two other patients who developed erythema seen over the area of ablation at their 1-week postoperatively follow-up. They were otherwise asymptomatic. Although the suspicion for cellulitis was low, both were given antibiotics.

Cosmesis
Although cosmesis from group II was not directly measured, subjective results appeared to be good to excellent, with the exception of the patient who sustained the significant burn that healed readily with local management. Surprisingly, in a majority of patients, the ablation zone was not palpably different than that expected for a lumpectomy. The patient with prior XRT had volume loss with reexcision such that her cosmetic result is good but not excellent. Futures studies plan to directly assess cosmesis.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Standard therapy for breast cancer often requires a multimodality approach that may include surgery, XRT, hormonal therapy, immunotherapy, and/or chemotherapy. The paradigm of lumpectomy followed by XRT was a major advance in the treatment of breast cancer, offering better cosmesis while maintaining equivalent local and systemic recurrence compared with modified radical mastectomy.6,32–39 Multiple studies have indicated the superiority of negative margins in maintaining local control.4,40 Recently introduced ablative techniques seek to further improve cosmesis via percutaneous needle ablation (reviewed in Singletary, et al.).26 All these techniques are predicated on extirpation of the primary tumor and a margin of normal tissue around the tumor. However, problems associated with ablative techniques include the undetermined degree of ablation needed to kill the tumor and the necessary margin around it, the lack of complete tumor histopathology, and the need for more tissue for newer gene studies that can better predict the risk of recurrence. eRFA represents a new paradigm based on a combination of old and new technologies—lumpectomy and RFA. Unlike percutaneous ablation techniques, eRFA allows lesion removal, full histopathology, and open margin ablation under visual guidance. Removing less volume of tissue from the breast allowed for improved subjective cosmesis in this group of patients whether they received XRT or not.16 Performance of the primary excisional biopsy and its pathologic evaluation is a key component in the oncologic and cosmetic success of BCS. For patients with resectable disease, all histologic types of breast cancer are eligible for BCS, and the chosen approach to local therapy depends on tumor location and size and the patient’s attitude toward breast preservation.

The oncologic importance of negative margins is related to the significant increase in LRR that exists when even focally positive margins are not reexcised, based on several, well-controlled retrospective studies (reviewed in Klimberg, et al.).40 Despite this evidence, most centers report a rate of positive margins between 20% and 55% on the initial diagnostic biopsy.1–3 A report from Japan that evaluated serial sections from the lumpectomy sites of mastectomy specimens found that the positive margin rate was 95%.41 Characteristics such as large tumor size, positive axillary nodes, extensive intraductal component, palpable tumor, and lobular histology correlate with an increased need for reexcision following BCS.14 Thus, patients with these characteristics may benefit from excision with wider margins, which necessitates removing more tissue and can lead to decreased cosmetic results.23 eRFA can help avoid reexcision by ablating occult residual disease without further excision at the time of the first operation.

The cosmetic issue is important because the best cosmetic results are obtained at the time of the initial operation and with a single excision. The volume of resected breast tissue has been shown to be directly correlated with the ultimate cosmetic outcome,16 and the volume of resected breast tissue is generally greater with a reexcision than with a single, adequate primary excision of tumor mass. The average volume of a lumpectomy is ~108 cc, which equates to a 6x6-cm dimensional removal of tissue [4/3{pi}(r)3]. Taking an additional 1 cm around the mass, as is done with shaved margins, more than doubles the amount of tissue removed (~256 cc). Surprised by the subjective improvement in cosmesis in our study, we hypothesized that the eRFA tissue, although for the most part resorbed, leaves a "matrix" that keeps the cavity bed from involuting. Future studies are objectively assessing cosmesis in these groups of patients.

The main problem with lumpectomy is that there is no flawless way to examine margins, particularly intraoperatively. 42,43 Pathologically, there is no standardized sampling method; most noncytologic methods assess only 10–15% of the surface of a relatively rounded breast lesion.13 Further, there is no standardized definition of what constitutes a "negative margin" although a majority would agree that 3 mm is an important metric to reduce recurrence.4,40,44 Carter suggested that it would take 3,000 6-µm-thick sections to fully evaluate the margins of a 2-cm breast biopsy, an impossible task intraoperatively and a formidable and impractical task postoperatively.13 Thus, presently available techniques provide only an estimation of margin status. Even when permanent pathology shows a negative margin, reexcision may show disease in ~25% of cases.14,15 Such occult disease is what eRFA targets.

Preliminary data reported here suggest that a newly developed supplemental technique—eRFA—may offer the best intraoperative opportunity to ensure negative margins in patients with breast cancer without compromising cosmesis. eRFA ablates the perimeter of the cavity to create an additional tumor-free zone, or margin, following optimal resection, without further tissue removal at the time of the first operation (Fig. 1Go).

Several randomized trials33–39 and a meta-analysis45 have demonstrated equivalent outcomes for lumpectomy + XRT and mastectomy. The addition, XRT following lumpectomy significantly decreases local recurrences, but long-term differences in survival in comparison with mastectomy are not affected. The Early Breast Cancer Trialist’s Collaborative Group45 recently reported on the effects of XRT and of differences in the extent of surgery for early breast cancer on LR and 15-year survival, compiling data from more than 78 randomized trials. The group concluded that differences in local treatment that substantially affect LRR would avoid approximately one breast cancer death over the next 15 years for every four LRs avoided and should reduce 15-year overall mortality rates.

Veronesi et al., in an effort to show that removing more versus less breast tissue was better, published a paper demonstrating that quadrantectomy + XRT had a lower recurrence rate than did lumpectomy + XRT but gave no details on margins or reexcisions.46 Arcangeli et al.47 showed comparable local control and overall survival with quadrantectomy and lumpectomy. All patients received XRT and had a boost (10–12 Gy), which may have improved local control, especially in the tumorectomy arm. The main caveat in most of these studies was that the lumpectomy arms had higher reresections to obtain negative margins. There have been at least six randomized trials that have compared BCS with and without adjuvant XRT, most in the absence of systemic therapy.6,12,48–51 Liljegren et al.50 looked at sector resection + XRT compared with sector resection alone. The 10-year local recurrence was 8.5% in the XRT group and 24% in the non-XRT group. This is lowered to 6.1% and 11.0%, respectively, for women > 55 years old. Margins were assessed as > 0.5 versus <0.5 in this study, with a relative rate (RR) of recurrence of 1.8 if the margin was <0.5. However, no other specific details about margins within each group were given. In the NSABP B–2130 that enrolled more than 1,000 patients with hormonally sensitive tumors ≤ 1 cm, the cumulative incidence of ipsilateral breast tumor recurrence over an 8-year period was 16.5% with tamoxifen alone, 9.3% with XRT and placebo, and 2.8% with XRT and tamoxifen. Margins in this study followed NSABP guidelines of no tumor on the inked margin. Lim et al. performed a prospective, nonrandomized study with a median follow-up of 86 months in 81 patients with unicentric T1 invasive mammary tumors without extensive intraductal component or lymphatic vessel invasion. All patients had negative margins >1 cm, all by re-excision, and none received XRT.31 Even in this highly select group of patients treated with conventional systemic therapy, LRR was 23%. High grade of the tumor but not volume of excision affected LRR. Taken together, these studies highlight the inadequacies of our pathological assessment, even when taking wide margins, and further, that an adjuvant therapy needs to be added to the tumor bed to reduce LRR. Our data suggest that eRFA can be an effective adjuvant to surgery, replacing reexcision in all but grossly positive cases and possibly substituting for XRT in favorable cases.

The primary effect of the addition of whole-breast XRT is a reduction of LRR at the tumor bed.32 Elsewhere recurrences in the breast appear to be affected to a much less extent, having comparable failures elsewhere in the breast in randomized controlled trials that compared BCS alone (1.5–5.5% elsewhere recurrence) with BCS + XRT (0.5–5.0% elsewhere recurrence).6,11,12,32 The need for whole-breast XRT has been predicated on pathologic data from Holland that demonstrated microscopic disease extended as much as 4 cm beyond the primary tumor, mostly in T2 cancers.52 More recent data on T1 tumors using simulated lumpectomies demonstrated that disease was primarily within 10 mm of the main mass.53,54 Vicini et al.15 wanted to define the clinical target volume for brachytherapy. In a consecutive study review of 607 patient with stage I or II disease, 441 patients who underwent reexcision were identified, 134 of whom had negative initial margins. Thus, nearly half of the original patients underwent reexcision for positive margins. In 90% of 134 patients with negative initial lumpectomy margins (per NSABP criteria, not at inked margin) at resection, if any residual disease was present (38.2% of cases), it was limited to <10 mm from the edge of the original lumpectomy margin. Results of several small series with 5-year follow-up indicate no difference in LRR between brachytherapy (partial-breast irradiation) and historic LRR after whole-breast irradiation, leading cooperative research groups to accept brachytherapy as a treatment option comparable with standard XRT and testing in the NSABP B-39 randomized trial.17–19,55,56 eRFA was designed to target this same 1-cm therapeutic zone around the lumpectomy cavity.

In the present study, there were no local recurrences in the tumor bed. Since most recurrences appear within the first 2 years, eRFA compares very favorably with brachytherapy as an adjuvant therapy. There were two elsewhere recurrences in patients who did not receive XRT. One could postulate that whole-breast XRT may have benefited these patients, but there is evidence that whole-breast XRT has no effect on elsewhere recurrences in the breast.6,11,12,30 Further, a preoperative MRI would have detected the multicentric nature of both of these patients.

The rationale for using percutaneous RFA in breast cancer is based on promising results seen in several other tumor types, including liver, bone, brain, kidney, pancreas, and prostate (reviewed in Wood et al.).20 Several trials of percutaneous RFA in patients with breast cancer have also yielded promising results (Table 1Go). Complete coagulative necrosis was noted in 86–100% of patients. Treatment was well tolerated, with few treatment-related complications noted and with excellent cosmesis.21–27 Nonetheless, several limitations of percutaneous ablation must be addressed before this technique can be considered a definitive treatment modality in breast cancer. Accurate 3D pathologic reconstruction is needed to assure complete tumor ablation prior to treating breast carcinoma by in situ ablation only. In addition, follow-up imaging remains problematic in detecting residual or recurrent disease. eRFA overcomes imaging and targeting issues by removing the main tumor and using RF to ablate the margin only. eRFA of margins also allows for this treatment to be performed to achieve better margins in any size tumor that is eligible for lumpectomy. eRFA is also advantageous in that it is easy to perform and technically easy to learn. Because of the low cost of eRFA, this is a technique that will readily and easily be disseminated to general practice, rural areas, and even Third World countries where mastectomy is sometimes the only option.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Trials of Percutaneous Radiofrequency Ablation (RFA) in Breast Cancer
 
In this report, we combined two available and reliable techniques, lumpectomy and RFA, to provide full histology and clear margins with better cosmesis. Our strategy, eRFA, includes both cancer excision and tumor-bed ablation at the excision site without removing large volumes of tissue, resulting in improved cosmesis. Further, 1-cm circumferential cavity ablation may provide better local control when compared with lumpectomy alone. We also hypothesize that eRFA alone may provide local control comparable with that of brachytherapy. The consistency and accuracy of this technique demonstrated in preclinical data in ablating tumor lumpectomy minimizes positive margins, thus avoiding repeat surgeries. The data we presented also suggests that eRFA alone may yield outcomes comparable with brachy-therapy, but this needs further follow-up.17–19,55,56 A vast array of techniques can be used to remove breast lesions. Palpation, needle-localization excisional breast biopsy (EBB), US-guided EBB, and all techniques used to direct the excision. Some surgeons utilize intraoperative pathology to redirect immediate excision of potentially positive margins. However, the end results of the surgery depend on the ability to pathologically determine the topography of the lumpectomy specimen and the presence of residual disease. eRFA may actually achieve superior local control when added to traditional methods because the lesion excision and ablation are pathology independent. In multiple studies, reexcision of focally positive, close, or even negative margins reveals residual disease in 25% of patients,14 even when undetected ablation should obliterate this disease, given that in a majority of T1 lesions, the disease is within 10 mm of the primary mass.53,54 Cosmesis, when tested, will also be improved since this procedure removes less tissue. RFA is user friendly, as it does not require a technician. A major advantage is that patients can receive all the therapy intraoperatively. eRFA will also mean less emotional trauma and less time away from work, as most patients do not have to return to the operating room for additional procedures.

eRFA creates a 1-cm margin around the cavity by providing consistent and thorough heating of the healthy breast tissue surrounding the cavity site. The use of RFA is not expected to increase risks associated with lumpectomy, such as bleeding, wound healing, infection, incision scarring, and anesthesia-related complications. Potential advantages to this treatment include reduced rate of reexcision due to positive or close margins, better cosmesis due to reduced volume of excised tissue and avoidance of XRT, outcomes potentially equivalent to brachytherapy in favorable tumors, replacement for boost in XRT, and salvage treatment for LRR in the previously irradiated breast.

Summary
Short-term follow-up suggests that in patients with early breast cancer, eRFA is safe and can reduce the need for re-excision surgery to achieve a negative margin. eRFA may represent a new paradigm in achieving optimal breast conservation during the first surgery. These single-site pilot data demonstrate the feasibility of the eRFA technique. A proposed multi-center trial will demonstrate the feasibility of learning and applying this simple technique to aid in achieving negative margins at multiple sites, as well as confirming decreased recurrence in a homogenous group of patients. The long-term objective of this trial is to lay the foundation for a multi-center, randomized trial that will lead to clinical use of our innovative treatment paradigm allowing improved treatment of early breast cancer.

Received for publication July 30, 2006. Accepted for publication July 31, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Mokbel K, Ahmed M, Nash A, Sacks N. Re-excision operations in nonpalpable breast cancer. J Surg Onc 1995; 58(4):225–8.[Medline]
  2. Clark K, Le MG, Sarrazin D, Lacombe MJ, Fontaine F, Travagli JP, May-Levine F. Analysis of local-regional relapses in patients with early breast cancers treated by excision and radiotherapy: experience of the Institute Gustave-Roussy. Int J Radiat Oncol Biol Phys 1985; 11:137–45.[Medline]
  3. Hustreich DJ, Dunn JM, Armstrong JS, et al. Diagnostic and therapeutic aspects of fine wire localization biopsy for impalpable breast cancer. Br J Surg 1992; 79:1038–41.[Medline]
  4. Singletary ES. Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Am J Surg 2002; 184:383–93.[CrossRef][Medline]
  5. Fisher ER, Anderson S, Tan-Chiu E, Fisher B, Eaton L, Wolmark N. Fifteen-year prognostic discriminants for invasive breast carcinoma: national surgical adjuvant breast and bowel project protocol-06. Cancer 2001; 91(Suppl 8):1679–87.[CrossRef][Medline]
  6. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347(16):1270–1.[Free Full Text]
  7. Arriagada R, Le MG, Rochard F, Contesso G. Conservative treatment versus mastectomy in early breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer Group. J Clin Oncol 1996; 62:596–602.
  8. Poggi MM, Danforth DN, Sciuto LC, et al. Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial. Cancer 2003; 98:697–702.[CrossRef][Medline]
  9. Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001; 345:1378–87.[Abstract/Free Full Text]
  10. Malmstrom P, Holmberg L, Anderson H, et al. for the Swedish Breast Cancer Group. Breast conservation surgery, with or without radiotherapy, in women with lymph node-negative breast cancer: a randomised clinical trial in a population with access to public mammography screening. Eur J Cancer 2003; 39:1690–7.[CrossRef][Medline]
  11. Veronesi U, Luini A, Del Vecchio M, et al. Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. N Engl J Med 1993; 328:1587–91.[Abstract/Free Full Text]
  12. Clark RM, Whelan T, Levine M, Roberts R, et al. Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: an update. Ontario Clinical Oncology Group. J Natl Cancer Inst 1996; 88:1659–64.[Abstract/Free Full Text]
  13. Carter D. Margins of "lumpectomy" for breast cancer. Hum Pathol 1966; 17:330–2.
  14. Jardines L, Fowble B, Schultz D, Mackie J, Buzby J, Torosian M, Daly J, Weiss M, Orel S, Rosata E. Factors associated with a positive reexcision after excisional biospy for invasive breast cancer. Surgery 1995; 118(5):803–9.[CrossRef][Medline]
  15. Vicini FA, Kestin LL, Goldstein NS. Defining the clinical target volume for patients with early-stage breast cancer treated with lumpectomy and accelerated partial breast irradiation: a pathologic analysis. Int J Radiat Oncol Biol Phys 2004; 60(3):722–30.[CrossRef][Medline]
  16. Wazer DE, DePetrillo T, Schmidt-Ullrich R, et al. Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 1992; 10:356–63.[Abstract/Free Full Text]
  17. Polgar C, Sulyok Z, Fodor J, et al. Sole brachytherapy of the tumor bed after conservation surgery for T1 breast cancer: five-year results of a phase I–II study and initial findings of a randomized phase III trial. J Surg Oncol 2002; 80:121–8.[CrossRef][Medline]
  18. Vicini FA, Baglan KL, Kestin LL, et al. Accelerated treatment of breast cancer. J Clin Oncol 2001; 19:1993–2001.[Abstract/Free Full Text]
  19. Kini V. Balloon breast brachytherapy – Review of current data. Brachytherapy 2005; 4(3):224–9.[CrossRef][Medline]
  20. Wood BJ, Ramkaransingh JR, Fojo T, Walther MM, Libutti SK. Percutaneous tumor ablation with radiofrequency. Cancer 2002; 94(2):443–51.[CrossRef][Medline]
  21. Jeffrey SS, Birdwell RL, Ikeda DM, et al. Radiofrequency ablation of breast cancer: first report of an emerging technology. Arch Surg 1999; 134:1064–8.[Abstract/Free Full Text]
  22. Izzo F, Thomas R, Delrio P, et al. Radiofrequency ablation in patients with primary breast carcinoma: a pilot study in 26 patients. Cancer 2001; 92:2036–44.[CrossRef][Medline]
  23. Fornage BD, Sneige N, Ross MI, et al. Small (2-cm) breast cancer treated with US-guided radiofrequency ablation: feasibility study. Radiology 2004; 231:215–24.[Abstract/Free Full Text]
  24. Burak WE Jr, Agnese DM, Povoski SP, et al. Radiofrequency ablation of invasive breast carcinoma followed by delayed surgical excision. Cancer 2003; 98:1369–76.[CrossRef][Medline]
  25. Hayashi AH, Silver SF, van der Westhuizen NG, et al. Treatment of invasive breast carcinoma with ultra-sound-guided radiofrequency ablation. Am J Surg 2003; 185:429–35.[CrossRef][Medline]
  26. Singletary SE, Fornage BD, Sneige N, et al. Radiofrequency ablation of early-stage invasive breast tumors: an overview. Cancer 2002; 8:177–80.
  27. Noguchi M, Earashi M, Fujii H, et al. Radiofrequency ablation of small breast cancer followed by surgical resection. J Surg Oncol 2006; 93:120–8.[CrossRef][Medline]
  28. Celis JE, Celis A. Cell cycle-dependent variation in the distribution of the nuclear protein cyclin proliferating cell nuclear antigen in cultured cells: subdivision of S phase. Proc Natl Acad Sci USA 1985; 82:3262–6.[Abstract/Free Full Text]
  29. Korourian S, Klimberg S, Henry-Tillman R, et al. Assessment of proliferating cell nuclear antigen activity using digital image analysis in breast carcinoma following magnetic resonance-guided interstitial laser photocoagulation. Breast J 2003; 9(5):409–13.[CrossRef][Medline]
  30. Smith TE, Lee D, Turner BC, et al. True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management. Int J Radiat Oncol Biol Phys 2000; 48:1281–9.[CrossRef][Medline]
  31. Lim M, Bellon JR, Gelman R, et al. A prospective study of conservative surgery without radiation therapy in select patients with Stage I breast cancer. Int J Radiat Oncol Biol Phys 2006; 65(4):1149–54.[CrossRef][Medline]
  32. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347:1233–41.[Abstract/Free Full Text]
  33. Blichert-Toft M, Rose C, Andersen JA, et al. Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr 1992; 11:19–25.
  34. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002; 347:1227–32.[Abstract/Free Full Text]
  35. Veronesi U, Salvadori B, Luini A, et al. Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomized trial on 1,973 patients. Eur J Cancer 1995; 31A:1574–9.[CrossRef]
  36. van Dongen JA, Voogd AC, Fentiman IS, et al. Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 2000; 92:1143–50.[Abstract/Free Full Text]
  37. van Dongen JA, Bartelink H, Fentiman IS, et al. Randomized clinical trial to assess the value of breast-conserving therapy in stage I and II breast cancer, EORTC 10801 trial. J Natl Cancer Inst Monogr 1992; 11:15–18.
  38. Jacobsen JA, Danforth DN, Cowan KH, et al. Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995; 332:907–11.[Abstract/Free Full Text]
  39. Sarrazin D, La MG, Arriagada R, et al. Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 1989; 14:177–84.[CrossRef][Medline]
  40. Klimberg VS, Harms S, Korourian S. Assessing margin status. Surg Oncol 1999; 8(2):77–84.[CrossRef][Medline]
  41. Haga S, Makita M, Shimiza T, et al. Histopathological study of local residual carcinoma after simulated lumpectomy. Surg Today 1995; 25:329–33.[CrossRef][Medline]
  42. Holaday WJ, Assor D. Ten thousand consecutive frozen sections: a retrospective study focusing on accuracy and quality control. Am J Clin Pathol 1974; 61:769–77.[Medline]
  43. Klimberg VS, Westbrook KC, Korourian S. Use of touch preps for diagnosis and evaluation of surgical margins in breast cancer. Ann Surg Oncol 1998; 5:220–6.[Abstract]
  44. Freedman GM, Fowble BL, Hanlon A, et al. Patients with early stage invasive cancer with close or positive margins treated with conservative surgery and radition have an increased risk of breast recurrence that is delyed by adjuvant systemic therapy. Int J Radiat Oncol Biol Phys 1999; 44:1005–15.[CrossRef][Medline]
  45. Early Breast Cancer Trialist’s Collaborative Group. Lancet 2005; 366;2087–105.[Medline]
  46. Veronesi U, Volterrani F, Luini A, et al. Quadrantectomy versus lumpectomy for small size breast cancer. Eur J Cancer 1990; 26(6):671–3.[Medline]
  47. Arcangeli G, Micheli A, D’Angelo L, Giovinazzo G, Arcangeli G, Tersigni R, Comandini E, Scala T, Lopez M, Mauri M, D’Aprile M. Conservative surgery and radiotherapy in early stage breast cancer: a comparison between tumourectomy and quadrantectomy. Radiother Oncol 1998; 46(1):39–45.[CrossRef][Medline]
  48. Veronesi U, Marubini E, Mariani L, et al. Radiotherapy after breast-conserving surgery in small breast carcinoma: Long-term results of a randomized trial. Ann Oncol 2001; 12:997–1003.[Abstract/Free Full Text]
  49. Holli K, Saaristo R, Isola J, et al. Lumpectomy with or without postoperative radiotherapy for breast cancer with favourable prognostic features: Results of a randomized study. Br J Cancer 2001; 84:164–9.[CrossRef][Medline]
  50. Liljegren G, Holmberg L, Bergh J, et al. 10-year results after sector resection with or without postoperative radiotherapy for stage I breast cancer: A randomized trial. J Clin Oncol 1999; 17:2326–33.[Abstract/Free Full Text]
  51. Fisher B, Bryant J, Dignam JJ, et al. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 2002; 20(20):4141–9.[Abstract/Free Full Text]
  52. Holland R, Veling SH, Mravunac M, Hendriks JH. Histologic multifocality of Tis, T1–T2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 1985; 56(5):979–90.[CrossRef][Medline]
  53. Ohtake T, Kimijima I, Fukushima T, et al. Computer-assisted complete three-dimensional reconstruction of the mammary ductal/lobular systems: implications of ductal anastomoses for breast-conserving surgery. Cancer 2001; 91(12):2263–72.[CrossRef][Medline]
  54. Ohtake T, Abe R, Kimijima I, et al. Intraductal extension of primary invasive breast carcinoma treated by brest-conservative surgery. Computer graphic three-dimensional reconstruction f the mammary duct-lobular systems. Cancer 1995; 76(1):32–45.[CrossRef][Medline]
  55. Ribeiro GG, Magee B, Swindell R, et al. The Christie Hospital breast conservation trial: an update at 8 years from inception. Clin Oncol (R Coll Radiol) 1993; 5:278–83.
  56. Veronesi U, Orecchia R, Luini A, et al. A preliminary report of intraoperative radiotherapy (IORT) in limited-stage breast cancers that are conservatively treated. Eur J Cancer 2001; 37:2178–83.[CrossRef][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Klimberg, V. S.
Right arrow Articles by Korourian, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Klimberg, V. S.
Right arrow Articles by Korourian, S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS