Cryoablation of Benign and Malignant Breast Tumors

Abstract: Cryoablation is a well established, FDA approved, minimally invasive treatment modality for fibroadenomas. Additionally, several pilot studies have shown its success in the treatment of small breast cancers. It is an outpatient office procedure performed percutaneously by placing a cryoprobe at the center of a tumor. A cryoprobe is a high-pressure, closed-loop gas expansion system, in which the metal probe is insulated, except for the tip. The tumor cells are killed due to direct injury from freezing and thawing of tissues as well as from damage to the microcirculation. It is an appealing alternative to surgery because it is minimally invasive, does not involve surgical resection or general anesthesia, is office based, has intrinsic analgesia, is inexpensive (relative to operative procedures), and has excellent cosmetic outcomes because patients do not undergo mastectomy. An additional advantage of cryoablation is its potential to enhance immunological response following the procedure. In the abscopal effect, the ablation of a single lesion triggers regression of distant metastases. It is thought that this results from the host immune system receiving antigens from the ablation bed, and acquiring immunity against the cancer. In a select group of patients with early breast cancer, it has the distinct advantage of potentially obviating the need for surgery and thereby resulting in improved cosmetic outcome for the patient. The best clinical results are achieved when small (<1.5 cm) invasive ductal tumors are treated with an ice ball larger than the tumor (i.e. with a 1 cm safety margin) and with an in situ component of less than 25%.

Key words: cryoablation, breast cancer, minimally invasive, fibroadenoma

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One of the most promising areas of current interventional research in the treatment of breast cancer is the development and validation of image-guided ablation as a nonsurgical minimally invasive therapy. This is in an effort to shift the treatment of breast cancer to include minimally invasive, cosmetically appealing, and cost-effective therapies. 

In many ways, the breast is the perfect organ for ablation. Covered only by skin with no intervening structures, the breast tissue can be compressed asymmetrically to achieve strategic skin-to-lesion geometries and imaged effectively with ultrasound.¹ Although breast conservation therapy allows mutilation to be avoided, the rate of negative cosmetic results after lumpectomy performed by means of “wide excision” is as high as 30%.^2,3

Cryoablation is an appealing alternative to surgery because it is minimally invasive, does not involve surgical resection, is office based, has intrinsic analgesia, is inexpensive (relative to operative procedures), and has excellent cosmetic outcomes.^4-6

Background

Cryoablation was the first ablative modality⁷ and also was the first ablative modality used for breast cancer.¹ The first-ever attempt at ablative therapy for resectable breast tumors was by Rand et al^7,8 who demonstrated a 70% reduction in local tumor recurrence after neoadjuvant cryoablation and surgical resection in a mouse model in 1985.¹ Initial experience with cryoablation for breast cancer centered on palliation of locally advanced disease.⁹ An initial preclinical and clinical study of in situ cryoablation led to several small series of cryoablation followed by surgical resection.¹⁰

Cryoablation for breast cancer was recently under investigation in the multicenter, phase II, American College of Surgeons Oncology Group Z1072 clinical trial.¹¹ This trial, the largest to date (100 patients, 20 clinical sites), was designed to determine if cryoablation can be successful in ablating stage 1 tumors, to study the efficacy of pre ablation MRI in determining tumor extent, and post ablation MRI in measuring completeness of the ablation and the presence of residual tumor. MRI was performed 14 days to 28 days after cryoablation, and a surgical lumpectomy was done 28 days after the MRI to evaluate for histologic residual tumor. Cryoablation was effective in 92% of targeted lesions and there was 100% ablation in all tumors <1 cm. The negative predictive value of MRI to determine residual invasive breast cancer or ductal carcinoma in situ was 81.2%.

Another ongoing study currently recruiting participants is the FROST (Freezing alone instead of Resection Of Small breast Tumors) trial. This study examines the use of cryoablation as an alternative to surgery in the treatment of early stage invasive breast cancer. The hypothesis is that cryoablation will completely ablate and destroy the tumor in a select population of women who may otherwise require surgery.

Cryoablation of benign fibroadenomas is a US Food and Drug Administration-approved procedure that is available for routine clinical use.¹² The implications of fibroadenoma for the interventional breast specialist are significant.¹ Almost 1 in 10 women will be diagnosed with a fibroadenoma in their lifetime, and about 500,000 women undergo fibroadenoma excision each year.^13,14 Fibroadenomas usually present clinically when they are between 1 cm and 3 cm in diameter, and they can be multiple and bilateral.¹⁵ Cryoablation can be performed in an office setting⁴ with only local anesthesia, whereas surgery is more expensive and may have poor cosmetic outcome.¹ Complete disappearance of the fibroadenoma within a year is achieved in 95% of patients, with excellent cosmetic results and without significant complications.¹⁶ A multi-institutional study reported high patient satisfaction in community settings.¹⁷

An additional advantage of cryoablation of malignant breast tumors is its potential to enhance immunological response following cryoablation.¹⁸ Early reports of abscopal effect in cryoablation patients with stage IV breast cancer by LePivert¹⁹ have sparked an entire field of immunomodulation research. In the abscopal effect, the ablation of a single lesion triggers regression of distant metastases. It is thought that this results from the host immune system receiving antigens from the ablation bed, and acquiring immunity against the cancer. In essence, the ablation creates a pool of presentable antigens as an in situ personalized cancer vaccine. Based on work by Matzinger,²⁰ this process is thought to be dependent on necrosis, which is disordered, and releases immunostimulatory intracellular contents that lead to dendritic cell maturation and macrophage activation.^21,22 It is possible that a cryoimmunologic effect may be protective against tumor recurrence or distant metastases or both, either alone or in combination with adjuvant immunotherapies.²³ 

Mechanism

Cryoablation is performed by placing a cryoprobe at the center of a tumor. A cryoprobe is a high-pressure, closed-loop gas expansion system, in which the metal probe is insulated, except for the tip. The cryoprobe is rapidly cooled by means of the Joule-Thomson effect (rapid expansion of a gas results in a change in the temperature of the gas), removing heat from the tissue in contact with the probe.²⁴

Although cryoablation refers to the freezing of tissues, cell damage is induced by a variety of mechanisms during both the freezing and thawing process, as well as indirect damage to the microcirculation. The method by which the cells die is related to the lowest temperature reached, the amount of time at subzero temperatures, and the number of freeze-thaw cycles (allowing the frozen tissue to thaw before freezing again).^25,26

Close to the cryoprobe, the freezing rates are high enough to induce freezing of the intracellular fluid, or intracellular ice formation.^27,28 This is a lethal event associated with irreversible membrane damage. Further from the probe, freezing rates are slower. Here, the extracellular fluid freezes, but the intracellular fluid has better protection by the lipid membrane. This causes cellular dehydration, by which osmotic forces shift pure water out of the cell. When the tissue is thawed, the intracellular compartment is hypertonic, and as the ice melts, fluid rushes into the damaged membranes, and the cells burst.^29,30

In addition, large ice crystals may form during recrystallization in the warming period, and these create direct shearing forces, which further disrupt the tissues. When the freezing is repeated, the damaged tissue conducts the cold more efficiently, increasing the area of necrosis beyond the first cycle. Cells not killed by direct cryoinjury may also suffer apoptotic cell death secondary to cryoinduced destruction of the microvasculature and post-thaw platelet aggregation and vascular stasis.³¹ Vessels with diameter larger than 0.5 cm avoid damage during cryoablation thanks to their own blood flow.³² Two freeze-thaw cycles of approximately 10 minutes each are used, which results in more effective tissue necrosis than 1 cycle.¹²

The total procedure time is approximately 30 to 40 minutes with the patient supine in comfortable position. The freezing (<40°C to  –160°C) is accomplished by rapid argon gas expansion (Joule-Thompson effect) or by liquid nitrogen, generating an ice ball of 4 to 7 cm, monitored by ultrasound. The ice ball has a discrete hyperechoic rim, depicting the border between frozen and unfrozen tissues. At least a 1-cm thick margin of ice beyond the tumor surface is necessary to assure complete cell death. 

During freezing, saline is injected between the ice ball and the skin to prevent skin damage that may occur if the ice ball rim is <0.5 cm from the skin.¹² The saline injections enable safe treatment of cancers that are close to the skin, unlike heat-based ablations.^23,33 Thawing of the ice ball is either passive or actively done using helium gas expansion, which enables removal of the probe from the ice ball (Figure 1).¹²

Conclusion

Cryoablation is a minimally invasive treatment modality for early stage breast cancer with a distinct advantage of potentially obviating the need for surgery in a select group of patients and thereby resulting in improved cosmetic outcome. Among minimally invasive therapies, an advantage of cryoablation over radiofrequency ablation is the ability to perform the procedure under local anesthesia and potentially on an outpatient basis. The best clinical results are achieved when small (<1.5 cm) invasive ductal tumors are treated with an in situ component of less than 25%.³⁴

Editor’s note: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no financial relationships or conflicts of interest regarding the content herein.

Manuscript received March 16, 2016; provisional acceptance given April 11, 2016; manuscript accepted May 9, 2016.

Address for correspondence: Geetika Klevos, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System, 1475 NW 12th Ave, Miami, FL 33136. Email: gmohin@med.miami.edu

Suggested citation: Klevos G, Collado-Mesa F, Net JM, Yepes MM. Cryoablation of benign and malignant breast tumors. Intervent Oncol 360. 2016;4(6):E95-E100.

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