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Annals of Surgical Oncology 9:326-332 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Focused Microwave Phased Array Thermotherapy for Primary Breast Cancer

Robert A. Gardner, MD, Hernan I. Vargas, MD, Jerome B. Block, MD, Charles L. Vogel, MD, Alan J. Fenn, PhD, Gary V. Kuehl, MD and Mariana Doval, MD

From Columbia Hospital (RAG, CLV, GVK, MD), West Palm Beach, Florida; Harbor-UCLA Medical Center (HIV, JBB), Torrance, California; and Massachusetts Institute of Technology (AJF), Lexington, Massachusetts.

Correspondence: Address correspondence and reprint requests to: Robert A. Gardner, MD, Medical Director, Center for Breast Care, Columbia Hospital, 4700 North Congress Ave., Suite 201, West Palm Beach, FL 33407; Fax: 561-881-9277; E-mail: rgbreastmd{at}aol.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS/FUTURE DIRECTIONS
 REFERENCES
 
Background: A pilot safety study of focused microwave phased array thermotherapy in the treatment of primary breast carcinomas was conducted.

Methods: Ten patients with breast carcinomas beneath the skin surface that ranged in maximal clinical size from 1 to 8 cm (mean, 4.3 cm) were treated with the breast compressed in the prone position. We planned to deliver a tumor thermal dose equivalent to 60 minutes at 43°C. Breast imaging and pathology data were used to assess efficacy.

Results: For the 10 patients, the mean tumor equivalent thermal dose was 51.7 minutes, the mean peak tumor temperature was 44.9°C, and the mean treatment time was 34.7 minutes. Ultrasound imaging demonstrated a significant reduction in tumor size (mean, 41%) 5 to 18 days after thermotherapy in 6 (60%) of 10 patients. A significant tumor response on the basis of reduction in tumor size or significant tumor cell kill occurred in 8 (80%) of 10 patients.

Conclusions: With sufficient skin cooling, delivery of focused microwave phased array thermotherapy is safe in treating breast carcinomas when used alone, and some potential efficacy was demonstrated at the tumor thermal doses administered. Increased tumor thermal dose efficacy studies in larger patient populations for improved breast conservation should be investigated.

Key Words: Thermotherapy • Hyperthermia • Adaptive microwave phased array • Breast cancer • Thermal dose


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS/FUTURE DIRECTIONS
 REFERENCES
 
Thermotherapy is sometimes used in a multimodality cancer treatment regimen to enhance the effects of radiotherapy or chemotherapy.1–8 In vitro studies demonstrate that human cell lines can be significantly damaged by heat-alone treatment provided that temperatures in the range of at least 45°C to 53°C can be achieved for sufficient time.9 A phase I study of heat-alone thermotherapy that used focused microwaves for treatment of primary breast cancer was the subject of a recent clinical investigation.10 We hypothesized that the use of thermotherapy to treat breast carcinomas can be effective in several ways and that, in most cases, the heat treatment must be capable of simultaneously reaching widely separated regions within the breast. Heating large volumes of the breast before surgery could destroy many or all of the microscopic carcinoma cells in the breast and reduce cancer recurrence, which is similar to the way full-breast radiotherapy is used after surgery to destroy microscopic residual cancer cells.11–15 With early-stage breast cancer, heating the tumor and killing a large percentage or all of the tumor cells before surgery may improve the margins and may reduce the possibility of inadvertently seeding viable cancer cells during the surgical procedure, thus reducing local recurrences in the breast. Locally advanced breast carcinomas are usually treated with mastectomy.16 Analogous to the use of preoperative chemotherapy,17 preoperative thermotherapy treatment alone or preoperative thermochemotherapy of locally advanced breast cancer may reduce the tumor size sufficiently to allow a less invasive surgical procedure to be performed. Eventually, with a sufficient thermal dose applied in a few treatments, preoperative thermotherapy treatment of locally advanced breast cancer or early-stage breast cancer may destroy the tumor and completely eliminate the need for any further breast surgery or perhaps even radiotherapy.

Microwave energy can preferentially heat and damage high–water content breast carcinomas, compared with the heating that occurs in lower–water content normal breast tissue.18–20 Experimental studies support the concept that tumor cell heating alone for 60 minutes at 43°C is tumoricidal and that the period of time to kill tumor cells decreases by a factor of 2 for each degree increase in temperature above approximately 43°C.21,22 Thus, a 60-minute treatment at 43°C can be reduced to only approximately 15 minutes at 45°C, which is often referred to as an equivalent thermal dose (CEM43° C, cumulative equivalent minutes relative to 43°C). The aim of this phase I study was to determine whether a 60-minute equivalent thermal dose could be used to safely heat, damage, and reduce the size of primary breast carcinomas before surgery. Tumor temperatures desired in this study were in the range of 45°C to 47°C.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS/FUTURE DIRECTIONS
 REFERENCES
 
To heat the compressed breast, two microwave phased array waveguide applicators23,24 were used, as depicted in Fig. 1. The waveguide applicators were spaced a few millimeters from the patients’ skin and contained internal fans that provided air cooling through the waveguide aperture. An E-field feedback probe25 was used in focusing26–31 the microwaves adaptively at the central tumor depth d, and a temperature feedback probe was used to adjust the microwave power level to heat the tumor to a desired temperature. Breast compression has a number of advantages for thermotherapy treatments. Use of breast compression results in less penetration depth required to achieve deep microwave heating and reduces blood flow, which improves the ability to rapidly heat tissue. Compressing the breast to a flat surface with an acrylic plastic material32 improves the transfer of microwave energy from the applicators to the breast tissue. Cooling the breast compression plates and skin with air during thermotherapy treatments helps reduce the potential for skin-surface hot spots. Compressing the breast with the patient in a prone position, such as that used in stereotactic needle breast biopsy procedures, 33 maximizes the amount of breast tissue within the compression device and moves the breast lesion away from the chest wall. Compression immobilizes the breast tissue such that any potential patient motion complications are eliminated. The compression device, which includes a small aperture, allows ultrasound-imaging techniques to accurately locate the tumor region and to assist in the placement of E-field and temperature needle sensors. The amount of compression can be varied from approximately 4 to 8 cm to accommodate patient tolerance during treatment.



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  		FIG. 1. Block diagram for a dual-channel adaptive microwave phased array thermotherapy system for treating deep breast cancer. The breast-compression plates are made of an acrylic material transparent to microwaves. Air cooling through the rectangular waveguide applicators is used to reduce the skin temperatures. The applicators generate a focused E-field radiation pattern that will illuminate a large volume of breast tissue. High–water content breast carcinomas may heat more rapidly than the surrounding normal breast tissues when exposed to the microwave field.

 
For thermotherapy treatment, the tumor was centrally located within the apertures of the compression plates, as depicted in Fig. 2. After a local anesthetic (1% lidocaine) was infiltrated at the desired entry point on the breast skin, the skin was nicked approximately 2.5 mm in length with an 11 blade, and the E-field sensor catheter (1.65 mm outer diameter) was inserted at the same depth d below the skin surface as the tumor tissue site in the breast. Similarly, a temperature sensor catheter was inserted into the tumor. Five noninvasive temperature probes were taped to the skin surface and nipple. It was desired that peak surface temperatures should not exceed approximately 41°C to 42°C. To provide added protection against skin damage from the microwave fields, several auxiliary fans surrounding the breast provided additional airflow.



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  		FIG. 2. Diagram showing the geometry of a parallel-opposed compression plate, ultrasound window, microwave applicator (dashed rectangle), and probes used in the patient treatments. The breast tumor was positioned with ultrasound guidance to be centrally located within the square apertures of the compression plates in cranial-caudal, medial-lateral, or medial-lateral-oblique position. The E-field feedback probe was inserted vertically. The temperature feedback probe (probe 1) was inserted horizontally into the tumor. Probes 2, 3, 4, and 5 measured the skin temperatures, and probe 6 measured the nipple temperature.

 
The total thermal dose in the tumor was computer controlled and displayed on the monitor during the treatment. The treatment was completed when the desired thermal dose was delivered to the tumor or the maximal treatment time (40 minutes) was reached. To determine the effectiveness of the treatment (tumor size reduction and tumor damage), ultrasound imaging with the patient supine and the breast and breast tumor of each patient in a consistent orientation was performed by an ultrasound technician before and after the microwave thermotherapy was administered, and pathology from needle core biopsy (single sample) and posttreatment mastectomy tissue was used to estimate tumor cell kill. Tumor cell kill on the basis of ischemic tumor necrosis was estimated from hematoxylin and eosin pathology. M30 immunohistochemistry performed by Impath, Inc. (Los Angeles, CA) afforded a way to study efficacy of the treatment in tumor cells. M30 staining characteristics in the pre- and postthermotherapy tumor tissue were compared. Care was taken to avoid any areas of obvious ischemic necrosis when comparing results. The M30 immunoglobulin G2b monoclonal antibody (Roche Molecular Biochemicals, Indianapolis, IN) binds to a caspase-cleaved, formalin-resistant epitope of the cytokeratin-18 cytoskeletal protein produced during early apoptosis. The cytokeratin-18 molecule is a structural protein present in all epithelial cells. Prior studies in human carcinomas have shown that the M30 antibody reliably detects apoptosis when compared with terminal transferase-mediated dUTP nick end labeling and annexin V assays.34

Tumor cell kill on the basis of M30 tests was calculated by first equating the prethermotherapy ratio of the percentage of cells staining positive and cells not staining to the ratio of the postthermotherapy positive-staining cells and the expected percentage of cells not staining if there was no thermotherapy treatment (denoted by the variable x). Solving for the variable x, the percentage of tumor cell kill was calculated by subtracting x from the percentage of cells not staining and then normalizing this quantity by dividing by the percentage of cells not staining. For example, if B is the percentage of cells staining before thermotherapy and A is the percentage of cells staining after thermotherapy and lumpectomy, then it follows that x = A(100 - B)/B and the percentage cell kill, denoted K, caused by thermotherapy is expressed as K = [(100 - A) - x]/(100 - A).

A Food and Drug Administration (FDA) Investigational Device Exemption–approved two-channel 915-MHz microwave adaptive phased array thermotherapy system (Microfocus-1000 APA; Celsion Corporation, Columbia, MD) was used in this study. This treatment system produces a focused microwave field in the breast to heat and destroy high–water content malignant breast tumors and microscopic carcinomas. The total or CEM thermal dose22 relative to 43°C was calculated from the measured temperatures recorded by the thermocouple sensors in the tumor and on the skin—the desired tumor thermal dose for this study was a CEM43°C of 60 minutes.

Ten volunteer patients were treated from December 1999 to July 2000 at Columbia Hospital in West Palm Beach, FL, and Harbor–University of California–Los Angeles Medical Center in Torrance, CA, as part of an FDA-approved phase I clinical feasibility and safety study,10 with internal review board approval obtained at each hospital. After providing fully informed written consent, female patients with breast carcinomas in an intact breast received a single thermotherapy session and 5 to 27 days later underwent mastectomy. Patients were enrolled onto the study provided that the tumor was at least 1 cm beneath the skin surface and not attached to the chest wall.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS/FUTURE DIRECTIONS
 REFERENCES
 
Ten patients in this phase I study, ranging in age from 47 to 82 years (mean, 58.5 years) and with breast carcinomas ranging in size from 1 to 8 cm (mean, 4.3 cm; maximal dimension on the basis of clinical examination), received thermotherapy (Table 1). All patients completed the thermotherapy treatment. In these treatments, the breast tissue compression thickness ranged from 4.5 to 6.5 cm (mean, 5.6 cm).


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  		TABLE 1. Patients’ characteristics
 
The peak tumor temperature, thermal dose to tumor and skin, tumor size reduction on the basis of ultrasound, and tumor cell kill on the basis of pathology are listed in Tables 2 and 3. The measured tumor thermal dose ranged from 25 to 103 minutes (mean, 52 minutes), and the measured peak surface thermal dose ranged from 0 to 4.4 minutes (mean, .8 minutes). The microwave treatment time ranged from 12 to 40 minutes (mean, 34.7 minutes). During each treatment, the tumor temperature was increased significantly higher than that of the skin and nipple. Peak tumor temperature ranged from 43.3°C to 47.7°C (mean, 44.9°C), and the peak surface temperature for all sensors ranged from 37.2°C to 42.1°C (mean, 40.7°C); thus, the mean peak tumor temperature achieved was 4.2°C higher than the mean peak surface temperature. The measured tumor and peak surface temperature during treatment for patient 7 are shown in Fig. 3—for this patient, the peak tumor temperature reached was 47.7°C, and the peak skin temperature was only 41.6°C. The thermotherapy treatment achieved evidence of tumor size reduction in six patients and tumor necrosis in four patients.


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  		TABLE 2. Thermal parameter results
 


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  		FIG. 3. Measured temperature in tumor and peak surface temperature during thermotherapy treatment for patient 7.

 

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  		TABLE 3. Breast tumor response for a single thermotherapy dose
 
From M30 immunohistochemistry, we found in six of the eight responding tumors that there was a significant decrease in staining of the thermotherapy-treated tumor cells. Before thermotherapy, the percentage of tumor cells staining M30 positive ranged from 70% to 90% (mean, 81.7%; SD, 9.8%). After thermotherapy and lumpectomy, the percentage of tumor cells staining M30 positive ranged from 20% to 60% (mean, 31.7%; SD, 16%). The decreased postthermotherapy staining observed when compared with the pretreated tumor was probably related to a nonviable cellular stage beyond the detection of the M30 antibody. These observations should be corroborated with other complementary apoptosis stains (such as terminal transferase-mediated dUTP nick end labeling), which detect cellular products in later stages of apoptosis.34 Of the eight patients who responded with either tumor shrinkage or ischemic tumor necrosis, apoptosis-based cell kill was calculated from the pre- and postthermotherapy M30 stains and showed, in six patients, from 82% to 97% tumor cell kill (mean, 89.7%) in the cells that did not stain M30 positive.

Side effects and their presumed causes in this study were as follows. In the first three patients, only two auxiliary fans surrounding the breast were used to cool the skin and nipple; the peak surface temperature of 41.9°C (mean) occurred (at the upper limit of 42°C desired), and the peak surface thermal dose of 2.5 minutes (mean) occurred. In the subsequent patient treatments, up to four auxiliary fans cooled the skin and nipple, and this may have helped reduce the peak temperature (mean, 40.2°C) and thermal dose (mean, .09 minutes) in the surface tissues for patients 4 to 10. Limited (range, .6 x 1.5 cm to 1.2 x 3.5 cm) flap necrosis occurred in the first three patients and may have been due to the combination of thin skin flaps, the peak skin temperature, skin thermal dose, and the short time (7 to 8 days) between thermotherapy and mastectomy. The first three patients ranged in age from 57 to 67 years (mean, 64.3 years), and the subsequent seven patients ranged in age from 43 to 82 years (mean, 57.3 years). Because the difference in mean age between the first three patients and the last seven is only 10%, patient age does not seem to be a significant parameter for flap necrosis in this study. Additionally, neither prethermotherapy tumor size (on the basis of ultrasound measurements) nor tumor grade correlated with flap necrosis. A small blister (approximately 1 cm in diameter) occurred because of thermotherapy for patient 3; it healed completely with no treatment required and presented no special considerations during surgery.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS/FUTURE DIRECTIONS
 REFERENCES
 
Conservation surgery as the initial treatment of breast cancer is not applicable to patients with large tumors and causes a suboptimal breast cosmetic outcome in patients with medium-sized tumors or small breasts. Neoadjuvant chemotherapy is used to achieve tumor size reduction and breast conservation in many of these breast cancer patients; however, complete pathologic response is seldom achieved.17 Current breast conservation therapy consisting of lumpectomy and radiotherapy does not always eliminate all viable cancer cells leading to recurrence, and radiotherapy has numerous side effects. The use of thermotherapy in a preoperative setting could reduce tumor burden and improve pathologic response without added side effects.

Our study demonstrates that a significant thermal dose (mean CEM43°C, 52 minutes) can be delivered to breast carcinomas at a central depth with a reduced superficial thermal dose (mean CEM43°C, .8 minutes). In the 10 treatments, the peak tumor temperature ranged from 43.3°C to 47.7°C, and peak surface temperatures ranged from 37.2°C to 42.1°C.

To determine the effectiveness of the heat-alone thermotherapy, the results of imaging and pathology data were analyzed. Tumor size reduction ranging from 29% to 60% (mean, 41%) occurred, in 18 days or fewer, in 6 (60%) of 10 patients, on the basis of ultrasound measurements. Postthermotherapy (27 days or fewer) mastectomy specimens showed that, in 4 (40%) of the 10 treatments, significant ischemic tumor necrosis estimated at 40% to 60% (mean, 48%) of total tumor volume occurred, and in 6 of 8 patients, tumor cell kill estimated at 82% to 97% (mean, 89.7%), on the basis of apoptosis measurements, occurred. It is possible that a longer observation time after thermotherapy could have resulted in further tumor size reduction and increased tumor cell kill.

Breast carcinomas usually do not exhibit ischemic necrosis unless the neoplasm is very large, and the center of it, which is poorly perfused, can become necrotic. However, it is common for high-grade ductal carcinomas, in situ and invasive, to demonstrate comedonecrosis, which is morphologically and pathologically distinct from ischemic necrosis. No ischemic necrosis was observed in any of the tumors before thermotherapy, but some of the tumors did have comedonecrosis. In all four cases in which the treatment resulted in ischemic tumor necrosis, the mechanism may have been related to blood stasis inducing microthrombi, with subsequent hypoxia leading to ischemic necrosis.

The pathology data of this study suggest that achieving a 60-minute thermal dose and a peak temperature of >45°C is correlated with the onset of significant ischemic tumor necrosis and that a higher dose and peak temperature are required for increased ischemic tumor necrosis for advanced breast carcinomas. Significant apoptosis-based cell kill occurred for peak tumor temperatures in the range of 44°C to 46.5°C, with a thermal dose in the range of 40 to 67 minutes. Similar results were observed for in vitro thermotherapy studies in murine mastocytoma, demonstrating that cell death is caused by apoptosis for temperatures in the range of 43°C to 45°C and by necrosis for temperatures of 45°C to 47°C when heat is applied for 30 minutes.35 The two patients (patients 4 and 5) for whom thermotherapy had no size reduction or ischemic necrosis effect on the tumor received <60 minutes of an equivalent thermal dose and had peak tumor temperatures of <=45°C. Patients 4 and 5 had surgery after thermotherapy within the shortest period of time (6 and 5 days, respectively). It is possible that waiting a longer period of time after thermotherapy would have resulted in some tumor response for these two patients.


   CONCLUSIONS/FUTURE DIRECTIONS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS/FUTURE DIRECTIONS
REFERENCES
 
In these tests of a clinical focused microwave phased array thermotherapy system, 10 patients were treated, and a significant thermal dose was delivered to breast carcinomas 1 to 8 cm in maximal clinical dimension and located at a central depth in the compressed breast. Eight (80%) of 10 patients had a significant tumor response (on the basis of tumor shrinkage measured by ultrasound) or tumor cell kill (on the basis of necrosis and apoptosis measurements). A higher tumor thermal dose than that used in this study, or more than one treatment, will be required to attempt complete tumor cell kill. We note that the immunoglobulin G2b monoclonal antibody used in this study provided primarily a weak positive stain for early apoptosis—other antibodies could be investigated in future studies to provide a stronger stain and more accurately estimate the percentage tumor cell kill. Focused microwave phased array thermotherapy is promising, and the FDA has recently approved multicenter phase II efficacy studies at increased thermal doses and multiple thermotherapy treatments in a larger group of patients undergoing or desiring breast conservation; these studies are in progress.


   Acknowledgments
 
The authors thank the staff at Columbia Hospital and Harbor–University of California–Los Angeles Medical Center who supported these clinical studies and the 10 patients who volunteered for thermotherapy treatment. Supported by Celsion Corporation, Columbia, MD.


   Footnotes
 
Presented at the 54th Annual Meeting of the Society of Surgical Oncology, Washington, DC, March 15–18, 2001.

Received for publication March 15, 2001. Accepted for publication January 17, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS/FUTURE DIRECTIONS
 REFERENCES
 

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S. E. Singletary
Minimally Invasive Ablation Techniques in Breast Cancer Treatment
Ann. Surg. Oncol., May 1, 2002; 9(4): 319 - 320.
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