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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.03.059 on January 12, 2004

Annals of Surgical Oncology 11:139-146 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Focused Microwave Phased Array Thermotherapy for Ablation of Early-Stage Breast Cancer: Results of Thermal Dose Escalation

Hernan I. Vargas, MD, William C. Dooley, MD, Robert A. Gardner, MD, Katherine D. Gonzalez, RN, Rose Venegas, MD, Sylvia H. Heywang-Kobrunner, MD and Alan J. Fenn, PhD

From Harbor-UCLA Medical Center (HIV, KDG, RV), Torrance, California; The University of Oklahoma (WCD), Health Sciences Center, Oklahoma City, Oklahoma; Columbia Hospital (RAG), West Palm Beach, Florida; Martin-Luther University (SHH-K), Halle, Germany; and Massachusetts Institute of Technology (AJF), Lexington, Massachusetts.

Correspondence: Address correspondence and reprint requests to: Hernan I. Vargas, MD, Division of Surgical Oncology, Harbor-UCLA Medical Center, 1000 W. Carson Street, Torrance, CA 90509; Fax: 310-782-1562; E-mail: hvargas{at}ucla.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Tumor ablation as a means of treating breast cancer is being investigated. Microwave energy is promising because it can preferentially heat high-water-content breast carcinomas, compared to adipose and glandular tissues.

Methods: This is a prospective, multicenter, nonrandomized dose-escalation study of microwave treatment. Thermal dose was measured as (1) thermal equivalent minutes (cumulative equivalent minutes; CEM) of treatment relative to a temperature of 43°C and (2) peak tumor temperature. Microwaves were guided by an antenna-temperature sensor placed percutaneously into the tumor. Outcomes measured were pathologic response (tumor necrosis) side effects.

Results: Twenty-five patients (mean age, 57 years) were enrolled. The mean tumor diameter was 1.8 cm. Tumoricidal temperatures (>43°C) were reached in 23 patients (92%). Tumor size was unchanged after thermotherapy (P = not significant). Pathologic necrosis was achieved in 17 (68%) patients. Complete necrosis of the invasive component was achieved in two patients. One hundred forty CEM is predictive of a 50% tumor response, and 210 CEM is predictive of a 100% tumor response (P = .003). Univariate linear regression predicts that peak tumor temperatures of 47.4°C and 49.7°C cause a 50% tumor response and a 100% tumor response, respectively.

Conclusions: Thermotherapy causes tumor necrosis and can be performed safely with minimal morbidity. The degree of tumor necrosis is a function of the thermal dose. Future studies will evaluate the impact of high doses of thermotherapy on margin status and complete tumor ablation.

Key Words: Breast cancer • Ablation • Minimally invasive • Microwave • Cancer treatment


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Breast cancer treatment has changed considerably in the last three decades. Changes in therapy have followed changes in clinical presentation.1 Increased patient education and awareness, public advocacy, and the implementation of screening mammography have contributed to a decrease in the size of breast cancer.2 Therefore, less invasive procedures have been increasingly used for the treatment of breast cancer.3,4

Breast cancer tumor ablation as part of a multimodality approach in the treatment of breast cancer is a subject of recent interest.5,6 The use of thermal energy with radiofrequency,7 interstitial laser photocoagulation,8 focused ultrasound,9 or cryotherapy10 has demonstrated some success in achieving ablation of breast tumors. A previous study of heat-alone thermotherapy with externally applied focused microwaves for treatment of primary breast cancer demonstrated that tumor temperatures in the range of 45.1°C to 47.7°C produced tumor necrosis in 40% of patients, suggesting that higher thermal doses are required for tumor necrosis.11 Microwave energy is promising because it can preferentially heat and damage high-water-content breast carcinomas, compared with the lesser degrees of heating that occur in lower-water-content adipose and breast glandular tissues.12,13

The aim of this phase II study was to determine the minimum required thermal dose to safely heat and completely kill primary breast carcinomas before surgery. Tumor temperatures desired in this study were in the range of 46°C to 50°C, with the equivalent tumor thermal dose gradually increased from 80 minutes relative to 43°C while avoiding skin damage and other morbidity.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
Between May 2001 and July 2002, patients with invasive breast carcinoma seen at Harbor-University of California–Los Angeles Medical Center in Torrance, CA; The University of Oklahoma in Oklahoma City, OK; Columbia Hospital in West Palm Beach, FL; and Martin-Luther University in Hale, Germany, were invited to participate in this Food and Drug Administration–approved thermal dose-escalation safety and efficacy clinical trial. This study was approved and monitored by the human subjects committee at each participating institution. Other eligibility criteria included: (1) Karnofsky performance status >70%, (2) core needle biopsy–proven invasive breast cancer, (3) planned breast-conservation treatment, (4) visible tumor measurable by ultrasound, and (5) absence of involvement of the skin or pectoralis muscle. All patients were required to undergo counseling and sign written, informed consent.

Specific exclusion criteria were pregnancy, breast-feeding, and presence of breast implants, pacemakers, or defibrillators. Other exclusion criteria were (1) known bleeding diathesis, (2) laboratory evidence of coagulopathy (prothrombin time, international normalized ratio >1.5; partial thromboplastin time >50 seconds), (3) thrombocytopenia (platelet count <100,000/mm3), (4) anticoagulant therapy, or (5) evidence of chronic liver disease or renal failure.

Study Design and Treatment Plan
This study was designed as an uncontrolled, prospective, multicenter, nonrandomized dose-escalation study. Microwave treatment was performed with the patient in the prone position on an outpatient basis with local anesthesia. A Food and Drug Administration-approved two-channel 915-MHz focused 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 tumor tissue. The rationale for this approach of focused microwave phased array (FMPA) for tumor thermal ablation was previously described.14 The technique of application has been previously described.11 Patients were monitored for toxicity after each treatment.

Thermal Dose
Experimental studies support the concept that heating tumor cells for 60 minutes at 43°C is tumoricidal, and the period of time to kill tumor cells decreases by a factor of 2 for each degree increase in temperature above approximately 43°C.16 Thus, the thermal energy required for a 120-minute treatment at 43°C can be reduced to only approximately 3.75 minutes at 48°C, which is often referred to as equivalent thermal dose (CEM43°C; cumulative equivalent minutes relative to 43°C). The cumulative equivalent minutes (CEM) thermal dose was calculated from the measured temperatures recorded by the sensors in the tumor and on the skin—the desired tumor thermal dose during microwave heating for this study was in the range of 80 to 120 CEM. Once the desired thermal dose is achieved, the microwave power is reduced to 0, and breast compression is maintained during a 5-minute cool-down period. During this period, because of the thermal insulation of the surrounding breast tissues, the thermal dose continues to accumulate in the tumor.

Dose Escalation
Escalation of thermal dose was performed in cohorts of five patients at progressively increasing doses of 80, 100, and 120 CEM. Treatment of an additional 10 patients at the highest dose was planned if no dose-limiting toxicity was reached. All toxicities were graded and reported according to dose level, and toxicities were assessed after therapy.

Outcomes Measured
Physical examination of the breast and ultrasound assessment were performed before thermal therapy and before surgery. A complete clinical response was defined as the complete disappearance of all clinically and radiologically detectable malignant disease. A partial clinical response was defined as a 50% or more decrease from baseline in the product of the areas of the measurable breast tumor. A <50% decrease was defined as clinical stable disease. Progression of clinical disease was defined as a 25% increase in any lesion.

Tumor cell kill was based on tumor necrosis and was estimated from hematoxylin and eosin–stained histological sections from wide local excision of the primary breast tumor. Necrosis was estimated and expressed as a percentage of necrotic tumor areas in relation to necrotic and viable tumor areas.

Adverse events, vital signs, and laboratory measurements (complete blood count, blood urea nitrogen and creatinine, bilirubin, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, alkaline phosphatase, and routine chemistries) were monitored to evaluate the safety and tolerability of the thermal dose. Performance status was recorded after thermal therapy.

Statistical Analysis
A model to compute the percentage of tumor necrosis as a function of either tumor thermal dose or peak tumor temperature achieved was developed on the basis of univariate and multivariate linear regression to determine the best fit to the measured data.17 With this linear regression model, a straight line was determined that minimizes the sum of the squares of the difference between the model tumor necrosis and measured tumor necrosis data.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Twenty-five patients were enrolled in this study. Patient demographic and tumor characteristics are listed in Table 1. Twenty-four (96%) of 25 patients tolerated the thermotherapy treatment. Thermotherapy was stopped early in a patient assigned to 120 CEM, who experienced severe pain within the first 4 minutes of treatment.


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  		TABLE 1. Demographic and tumor characteristics of the study population
 
Tumor and skin temperature measurements for a typical case are depicted in Fig. 1. Tumoricidal temperatures (>43°C) were reached in 23 patients (92%). However, there were tumor temperature measurement errors in three cases caused by inaccurate probe placement or undesired probe movement during treatment. The breast tissue compression thickness ranged from 3.5 to 6.5 cm and was adjusted during microwave thermotherapy as necessary to maintain patient comfort. Patients underwent breast-conserving surgery on average 17 days after thermotherapy (range, 6–38 days).



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  		FIG. 1. Tumor and skin temperatures and power during thermotherapy treatment.

 
Clinical Response
The mean of ultrasound measurements of tumor size at baseline was 17.6 mm (range, 7–25 mm). There was no demonstrable clinical or radiological change in tumor size (P = not significant) with thermotherapy. The mean tumor size was 18.4 mm (range, 7–38 mm) after thermal therapy and before surgical excision. On the basis of standard criteria for radiological tumor volume change, 4 patients had a response; disease remained stable in 13, and there was clinical progression in 8. However, there was no correlation between clinical/ultrasonographic size changes and pathologic tumor response. The correlation between tumor necrosis and the change in tumor volume was .38 (P = .11).

Pathologic Response
There was evidence of pathologic necrosis in 17 (68%) patients. An example of the gross and histological tumor necrosis induced by microwave thermal therapy is depicted in Fig. 2A and B. There was complete ablation of invasive carcinoma in two cases. However, both patients had residual in situ breast cancer. There was one additional patient with a single cluster of residual tumor cells (tumor necrosis was estimated at 99.9%). The extent of necrosis in the other cases ranged from 25% to 90%. Tumor-free margins with breast conservation surgery were obtained in 24 (96%) patients. The degree of histological tumor response in the three cohorts of patients according to planned thermal dose is listed in Table 2.



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  		FIG. 2. Gross (A) and histological (B) sections of tumor necrosis induced by microwave thermal energy.

 

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  		TABLE 2. Histological tumor response in the three cohorts of patients according to planned thermal dose
 
Six of the 25 subjects were excluded from the efficacy analysis of thermal energy–induced pathologic necrosis due to inaccurate tumor temperature recordings in 4 cases and delivery of suboptimal thermal dose in 2 cases. Data for the 19 included patients are shown in Table 3. Eight patients received a cumulative thermal dose in the range of 158.9 to 206 minutes, and all had significant tumor necrosis (range, 60%–100%; mean, 84%). Nine patients received a thermal dose in the range of 107.8 to 147.8 minutes, and six (67%) of nine had tumor necrosis (range, 25%–95%; mean, 40%). Two patients received a thermal dose in the range of 82.8 to 97.2 minutes, and one (50%) of two had tumor necrosis (range, 0%–50%; mean, 25%). Fourteen (93.3%) of 15 patients receiving a peak tumor temperature of >=46.9°C had tumor necrosis (range, 25%–100%; mean, 72.1%).


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  		TABLE 3. Treatment parameters and degree of tumor necrosis
 
Linear regression analysis17 was performed to predict tumor response on the basis of thermal dose and peak temperature achieved. The percentage of tumor necrosis in relation to the thermal dose is expressed in Fig. 3. A thermal dose of 140 CEM is predictive of a 50% tumor response, and 210 CEM is predictive of a 100% tumor response (P = .003). The percentage of tumor necrosis in relation to the peak tumor temperature is noted in Fig. 4. The univariate linear regression model predicts that a peak tumor temperature of 47.4°C is predictive of a 50% tumor response and that a peak tumor temperature of 49.7°C is predictive of a 100% tumor response. The predicted thermal dose and peak tumor temperature for 0%, 50%, 85%, and 100% necrosis are listed in Table 4. Both peak tumor temperature and thermal dose show a statistically significant association with tumor necrosis. Thermal dose is the better predictor of tumor necrosis. Using a multivariate regression model containing both independent variables does not significantly improve the predictive power of the model. This is due in large of part to the high correlation between the treatment parameters (correlation, .60).



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  		FIG. 3. Pathologic tumor necrosis in relation to tumor thermal dose (cumulative equivalent minutes; CEM) for 19 patients. The dashed line is the linear regression fit (% necrosis = .719 CEM - 50.902) to the experimental data.

 


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  		FIG. 4. Pathologic tumor necrosis in relation to tumor peak temperature (Tp) for 19 patients. The dashed line is the linear regression fit (% necrosis = 19.128 Tp - 851.176) to the experimental data.

 

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  		TABLE 4. Projected thermal dose and peak tumor temperature required for 0%, 50%, 85%, and 100% necrosis of invasive breast carcinomas
 
Adverse Events
In the first cohort of patients scheduled to receive 80 CEM, three patients had one treatment and two patients were given two treatments. Thermotherapy was well tolerated. Short-lived erythema developed in the skin of the treated breast in two patients. In patients assigned to the 100-CEM thermal dose, three (60%) developed short-lived erythema, two (40%) experienced mild pain during treatment, and one (20%) developed a first-degree burn in the treated skin that completely healed and presented no special considerations during surgery.

In the last cohort of patients, scheduled to receive 120 CEM, one patient reported severe pain in the first 4 minutes of thermotherapy, and the treatment was stopped—the highest skin temperature was 37.2°C, and the tumor temperature was 39.2°C at the time the microwave energy was turned off. Seven (47%) patients experienced pain, four (27%) developed short-lived skin erythema, five (33%) developed edema of the breast or areola, and two developed skin thermal burns (first and third degree). The third-degree burn occurred over a small area (8-mm diameter) enclosing the focusing probe skin entry point, which was within the microwave field in proximity to one of the microwave applicators.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
There is increasing interest in the use of minimally invasive ablative techniques in the treatment of breast cancer.18 A new treatment paradigm in which systemic therapy may be followed by minimally invasive local therapy to eradicate any residual local tumor has been proposed and is the subject of research studies.19 This is seen as the next step in an evolution of therapy that is designed to offer less invasive means of therapy to patients presenting with small cancers that are detected as a result of screening practices.19

The objective of using minimally invasive techniques is to cause complete local tumor regression and long-term local control of breast cancer with minimal damage to the surrounding normal breast tissue. Other characteristics of the ideal treatment are that it must be an outpatient procedure using a percutaneous or transcutaneous application without the need for sedation or general anesthesia. The morbidity and local complications must be minimal.

Thermal ablation has taken a prominent role in minimally invasive approaches to treating neoplasms.18,19 Freezing may be achieved through cryoablation,10,20 whereas heat energy may be generated by the use of interstitial laser photocoagulation,8 radiofrequency-induced coagulation,21 focused ultrasound,9 or microwave ablation.11

The cytotoxic effects of hyperthermia using temperatures in the range of at least 45°C to 53°C have been demonstrated on a variety of cell types in vitro.22,23 Experimental studies support the concept that tumor cell heating alone for 60 minutes at 43°C is tumoricidal, and the period of time to kill tumor cells decreases by a factor of 2 for each degree increase in temperature above approximately 43°C.23 In fact, hyperthermia has a preferential toxic effect on tumor cells compared with normal tissues.23 There is also a differential response of normal versus tumor microcirculation to hyperthermia, leading to microvascular thrombosis within tumors at temperatures of 41°C.24 In the clinical setting, thermotherapy has been clinically used to enhance the effects of radiation or chemotherapy.25–30

Microwave energy is promising because it can preferentially heat and damage high-water-content breast carcinomas, compared with the lesser degrees of heating that occur in lower-water-content adipose and breast glandular tissues.31 The coherent microwave radiation from the two applicators used in this system oscillates at a rate of 915 MHz, and the timing (or relative phase) of the two waves emanating from the applicators is adjusted to achieve peak radiation at the focal point defined by the E-field probe located in the tumor. The fast oscillation of the microwave energy combined with the high electrical conductivity of breast carcinomas31 produces a significant amount of molecular friction in the breast carcinoma cells that generates heat and rapidly increases the temperature of the tumor.

In this clinical trial, two thirds of patients exhibited various degrees of coagulative necrosis that ranged from 25% to 100%. Complete ablation of invasive breast cancer was achieved in two cases, and there was only a residual cluster of cancer cells in one additional case. Success was achieved in the subset of patients receiving higher thermal doses. The main objective of this study of FMPA thermotherapy was to find the dose necessary to cause complete tumor ablation without clinically significant toxicity. The thermal dose was escalated in 25 patients. This study has established that both thermal dose and peak temperature show a statistically significant association with the presence of tumor necrosis in the wide local excision specimen. On the basis of this statistical model, 100% tumor cell death is expected when a thermal dose of 209.8 CEM and a peak tumor temperature of 49.7°C are achieved. Furthermore, the therapeutic window of FMPA takes place at a point where no significant toxicity is seen. Future studies conducted at therapeutic doses of FMPA will provide meaningful information regarding the success of this therapy on the basis of pathological response. Comparison with other means of percutaneous thermal ablation of breast cancer will then be possible. Success rates with other means of thermal ablation are in the range of 33%–96 %.7–11,21

Residual ductal carcinoma-in-situ was found in the two cases with complete ablation of the invasive carcinoma component on pathologic analysis. Elements of intraductal carcinoma may extend outside the tumor mass and may be difficult to detect before surgery.32 This is a potential pitfall of minimally invasive ablative approaches and has been documented with cryotherapy as well.10 Future studies of thermal ablation should select patients with invasive carcinoma with a lower risk of an intraductal carcinoma component on the basis of pretreatment mammography and percutaneous biopsy results.33,34

No uniform decrease in tumor size was observed in the short interval from thermal ablation to surgery, even in cases with a successful pathologic tumor response. Increases in tumor size were seen in eight cases. This size increase is the result of thermal injury and the development of tissue edema. Alternative approaches to measure the success of thermal ablation are essential if a nonsurgical treatment is contemplated. Imaging with mammography is unlikely to provide additional valuable information. Ultrasound is most valuable in providing easy targeting and placement of the sensors within the mass but may not provide information about the viability of the tumor. However, delayed contrast-enhanced magnetic resonance imaging has the potential to show the effects of treatment as areas of devascularization (nonenhancement) within the treated area.35 Alternatively, tissue sampling in follow-up with core biopsy or vacuum-assisted core biopsy may provide essential information about residual tumor.

In this study, FMPA was conducted by the placement of a percutaneous sensor catheter for focusing of the microwaves (E-field sensor) and measurement of tumor temperatures (temperature sensor). Temperature sensor positioning was not extensively evaluated in this study. However, in two cases, large areas of necrosis secondary to FMPA were located eccentrically to the tumor mass. A residual area of viable tumor was then marginally missed because of imperfect targeting. We agree with Izzo et al.,21 who, on the basis of their experience with radiofrequency ablation, have recognized the importance of accurate placement of the percutaneous probe in the success of percutaneous tumor ablation. In the future, FMPA has the potential of being a transcutaneous procedure that does not require the insertion of any needle-type devices, and targeting may be conducted on the basis of imaging alone.

An observation arising from this study is the 96% success in achieving negative margins, in comparison with reported incidences of positive margins of 4% to 44%.36–39 The two microwave applicators have rectangular apertures that face the compressed breast tissue.14 The effective microwave radiation field encompasses an approximately 6 x 8 cm area in the breast tissue in a plane parallel to the compression plates. In the compressed breast thickness dimension, the effective microwave field extends approximately 1.5 cm on either side of the focal target point in the tumor. This conformation has the potential for creating a large area of tumor cell kill. A hypothesis that requires critical study is whether the use of thermotherapy treatment before breast-conservation surgery provides significant tumor cell kill at the margins, is responsible for a low incidence of positive margins, and contributes to a reduction in the need for re-excision compared with surgery alone. This hypothesis is the subject of ongoing clinical trials. Thermal ablation with FMPA was well tolerated, and no significant complications were recorded.


   ACKNOWLEDGMENTS
 
The acknowledgments are available online in the fulltext version at www.annalssurgicaloncology.org. They are not available in the PDF version.


   FOOTNOTES
 
Presented at the 56th Annual Cancer Symposium from the Society of Surgical Oncology, Los Angeles, California, March 8, 2003.

This prospective, multicenter dose-escalation study determines the optimal dose to achieve tumor ablation during minimally invasive treatment of breast cancer with focused microwave phased array energy delivered transcutaneously.

Received for publication March 8, 2003. Accepted for publication October 3, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Edney JA. Breast cancer treatment for the future based on lessons from the past. Am J Surg 2002; 184: 477–83.[CrossRef][Medline]
  2. Cady B, Stone MD, Schuler JG, et al. The new era in breast cancer: invasion, size, and nodal involvement dramatically decreasing as a result of mammographic screening. Arch Surg 1996; 131: 301–8.[Abstract]
  3. 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]
  4. Vargas HI, Vargas MP, Khalkhali I. Sentinel node biopsy in the management of the axilla. Semin Breast Dis 2002; 5: 156–72.
  5. Singletary ES. Minimally invasive techniques in breast cancer treatment. Semin Surg Oncol 2001; 20: 246–50.[CrossRef][Medline]
  6. Hall-Craggs MA, Vaidya JS. Minimally invasive therapy for the treatment of breast tumors. Eur J Radiol 2002; 42: 52–7.[CrossRef][Medline]
  7. 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]
  8. Dowlatshashi K, Francescatti DS, Bloom KJ. Laser therapy for small breast cancers. Am J Surg 2002; 184: 359–63.[CrossRef][Medline]
  9. Huber PE, Jenne JW, Rastert R, et al. A new noninvasive approach in breast cancer therapy using magnetic resonance imaging-guided focused ultrasound surgery. Cancer Res 2001; 61: 8441–7.[Abstract/Free Full Text]
  10. Pfleiderer SO, Freesmeyer MG, Marx C, Kuhne-Heid R, Schneider A, Kaiser WA. Cryotherapy of breast cancer under ultrasound guidance: initial results and limitations. Eur Radiol 2002; 12: 3009–14.[Medline]
  11. Gardner RA, Vargas HI, Block JB, et al. Focused microwave phased array thermotherapy for primary breast cancer. Ann Surg Oncol 2002; 9: 326–32.[Abstract/Free Full Text]
  12. Joines WT, Zhang Y, Li C, Jirtle RL. The measured electrical properties of normal and malignant human tissues from 50 to 900 MHz. Med Phys 1994; 21: 547–50.[CrossRef][Medline]
  13. Campbell AM, Land DV. Dielectric properties of female human breast tissue measured in vitro at 3.2 GHz. Phys Med Biol 1992; 37: 193–210.[CrossRef][Medline]
  14. Fenn AJ, Wolf GL, Fogle RM. An adaptive phased array for targeted heating of deep tumors in intact breast: animal study results. Int J Hyperthermia 1999; 15: 45–61.[CrossRef][Medline]
  15. Reference deleted.
  16. Sapareto SA, Dewey WC. Thermal dose determination in cancer therapy. Int J Radiat Oncol Biol Phys 1984; 10: 787–800.[Medline]
  17. Armitage P, Berry G. Statistical Methods in Medical Research. 3rd ed. Oxford: Blackwell Science, 1994: 156–63, 283–311.
  18. Dowlatshashi K, Francescatti DS, Bloon KJ, et al. Image-guided surgery of small breast cancers. Am J Surg 2001; 182: 419–25.[CrossRef][Medline]
  19. Singletary SE. Minimally invasive ablation techniques in breast cancer treatment. Ann Surg Oncol 2002; 9: 319–20.[Free Full Text]
  20. Kaufman CS, Bachman B, Littrup PJ, et al. Office-based ultrasound-guided cryoablation of breast fibroadenomas. Am J Surg 2002; 184: 394–400.[CrossRef][Medline]
  21. Izzo F, Thomas R, Delrio P, et al. Radiofrequency ablation in patients with primary breast carcinoma. A pilot study of 26 patients. Cancer 2001; 92: 2036–44.[CrossRef][Medline]
  22. Gerhard H, Klinger HG, Gabriel E. Short term hyperthermia: in vitro survival of different human cell lines after short exposure to extreme temperatures. In: Streffer C, ed. Cancer Therapy by Hyperthermia and Radiation. Baltimore: Urban & Schwarzenberg, 1978: 201–3.
  23. Giovanella BC, Stehlin JS Jr, Morgan AC. Selective lethal effect of supranormal temperatures on human neoplastic cells. Cancer Res 1976; 36: 3944–50.[Medline]
  24. Dudar TE, Jain RK. Differential response of normal and tumor microcirculation to hyperthermia. Cancer Res 1984; 44: 605–12.[Abstract/Free Full Text]
  25. Vernon CC, Hand JW, Field SB, et al. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. Int J Radiat Oncol Biol Phys 1996; 35: 731–44.[CrossRef][Medline]
  26. Valdagni R, Amichetti M. Report of long-term follow-up in a randomized trial comparing radiation therapy and radiation therapy plus hyperthermia to metastatic lymphnodes in stage IV head and neck patients. Int J Radiat Oncol Biol Phys 1993; 28: 163–9.
  27. Overgaard J, Gonzalez Gonzalez D, Hulshof MCCH, et al. Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic Oncology. Int J Hyperthermia 1996; 12: 3–20.[Medline]
  28. van der Zee J, Gonzalez Gonzalez D, van Rhoon GC, van Dijk JDP, van Putten WLJ, Hart AAM. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumors: a prospective, randomised, multicentre trial. Lancet 2000; 355: 1119–25.[CrossRef][Medline]
  29. Takahashi M, Fujimoto S, Kobayashi K, et al. Clinical outcome of intraoperative pelvic hyperthermochemotherapy for patients with Dukes’ C rectal cancer. Int J Hyperthermia 1994; 10: 749–54.[Medline]
  30. Sugimachi K, Kuwano H, Ide H, Toge T, Saku M, Oshiumi Y. Chemotherapy combined with or without hyperthermia for patients with oesophageal carcinoma: a prospective randomized trial. Int J Hyperthermia 1994; 10: 485–93.[Medline]
  31. Chaudhary SS, Mishra RK, Swarup A, Thomas JM. Dielectric properties of normal and malignant human breast tissue at radiowave and microwave frequencies. Indian J Biochem Biophys 1984; 21: 76–9.[Medline]
  32. Holland R, Hendriks JH, Vebeek AL, Mravunac M, Schuurmans Stekhoven JH. Extent, distribution, and mammographic/histological correlations of breast ductal carcinoma in situ. Lancet 1990; 335: 519–22.[CrossRef][Medline]
  33. Cadman B, Ostrowski J, Quinn C. Invasive ductal carcinoma accompanied by ductal carcinoma in situ (DCIS): comparison of DCIS grade with grade of invasive component. Breast 1997; 6: 132–7.[CrossRef]
  34. Bagnall MJ, Evans AJ, Wilson AR, et al. Predicting invasion in mammographically detected microcalcification. Clin Radiol 2001; 56: 828–32.[CrossRef][Medline]
  35. Hall-Craggs MA. Interventional MRI of the breast: minimally invasive therapy. Eur Radiol 2000; 10: 59–62.[CrossRef][Medline]
  36. Recht A, Come SE, Henderson IC, et al. The sequencing of chemotherapy and radiation therapy after conservative surgery for early stage breast cancer. N Engl J Med 1996; 334: 1356–61.[Abstract/Free Full Text]
  37. Park CC, Mitsumori M, Nixon A, et al. Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence. J Clin Oncol 2000; 18: 1668–75.[Abstract/Free Full Text]
  38. Smitt MC, Nowels KW, Zdeblick MJ. The importance of lumpectomy surgical margin status in long term results of breast conservation. Cancer 1995; 76: 259–67.[CrossRef][Medline]
  39. Ryoo MC, Kagan AT, Wollin M, et al. Prognostic factors for recurrence and cosmesis in 393 patients after radiation therapy for early mammary carcinoma. Radiology 1989; 172: 555–9.[Abstract]




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