Abstract: Cryoablation has been successfully used to treat various type of solid tumors, including breast carcinomas. This ablation method has the advantage of being a minimally invasive procedure useful in various clinical situations, including early breast cancer and metastatic breast cancer, when co-morbidities preclude the use of surgical treatment. However, due to the small sample size of the available studies, reliable and definitive conclusions on the usefulness of cryoablation in patients with breast cancer could not be drawn. In fact, many aspects necessitate to be elucidated, regarding technical issues, indications, efficacy, imaging follow-up, and possible advantages over other percutaneous ablative methods. This review article has the aim to clarify the current evidence supporting cryoablation of breast cancer, and discuss the future perspectives, including those arising from the new studies on immunological effects related to cryoablation.


Keywords: cryoablation, breast cancer, ablation, treatment, interventional radiology


INTRODUCTION


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In recent years, there has been a surge of ablative methods for the treatment of different solid neoplasms. Those techniques were initially used as alternative to surgery in either inoperable patients or in those with metastatic disease in order to achieve cytoreduction of the primary tumor.1–5 Ablation techniques offer the advantage of being done percutaneously under image guidance, thus obtaining in general low rates of complications and patients’ discomfort. As regards breast cancer, a large amount of articles in the recent literature reports on the use of radiofrequency, microwave ablation, cryoablation, interstitial laser therapy, and focused ultrasound in different clinical scenarios.3,6–9 Among them, cryoablation represents an emerging treatment, which has been used in the treatment of both benign and malignant breast diseases. A systematic literature search using the PubMed, WOS, and Scopus databases was performed in June 2019 to identify studies in English language reporting on outcomes of cryoablation in patients with breast cancer. The following terms were used for the search: “cryoablation”, or “cryotherapy, or “cryosurgery”, and “breast cancer”, or “breast diseases”. The “related articles” function was used to broaden the search and all abstracts, citations, and studies scanned as well as the references of relevant articles were reviewed (see search strategy in Figure 1). The aim of this review is to provide a synthesis on the use of cryoablation as ablative treatment in breast cancer at different stages. In fact, some authors have assessed cryoablation in patients with metastatic disease, whereas others have used it in those who were unsuitable for surgery, or refused surgical treatment. More recently, cryoablation has been proposed as an alternative to surgery in selected patients with early breast cancer. In addition, studies investigating the correlations between cryoablation, immunotherapy, and systemic anti-tumoral agents have been reviewed.

CRYOABLATION TECHNIQUE AND APPLICATION IN BREAST CANCER

The efficacy of cryoablation is based on the cytotoxic effects of cold that produce both instant and delayed destruction of cellular ultrastructure. Tissue destruction occurs when tissues are frozen to lethal temperatures lower than −40°C.3,10–12 Cold temperatures result in increasing of intracellular osmolarity and freezing of extracellular water; this causes, in turn, drawing water out of the cells and cellular dehydration. During the passive thaw phase, cell swelling and subsequent rupture occurs. Additionally, ice crystals in the intracellular milieu damage organelles and plasma membranes. Cryoablation also damages tumor cells by causing endothelial cell dysfunction, microthrombus formation, ischemia, and platelet aggregation.1–5,13,14

Cryoablation consists of cycles of first freeze, a passive thaw phase, and a second freeze.12,15 It usually takes less than 45 mins to be completed. A second freeze is necessary because tissues that have been injured during the first freeze conduct cold temperatures more efficiently, thus enhancing the damaging effects of cold and expanding the area of tumor necrosis. The duration of the thaw phase varies according to the size and position of the tumor, the device in use, and the size of margins around the target lesion. It is known that breast cancer nodules require longer freeze time than fibroadenomas. In general, cryoablation of invasive breast cancer is supposed to create an ice ball extended at least 1 cm beyond the tumor margins. Breast cryoablation may be done with US, CT, or MRI guidance. Although the first cases were performed under MRI guidance,16,17 cryoablation is usually performed under US- or CT-guidance for probe(s) placement and monitoring the ice ball formation in the target lesion.8

Cryoablation can be carried out with little anesthesia, because the cooling produced by the probes provides analgesia. In fact, it can be also performed as an outpatient basis.8 Cryoablation is a minimally invasive method capable of obtaining satisfying aesthetical results.18 More importantly, it is a repeatable procedure in case of local relapse or incomplete ablation. Furthermore, it does not interrupt other systemic therapies, ie, systemic treatment for metastatic disease, and can act in synergy with them.1,19,20 Cryoablation is not without possible adverse effects. One of the disadvantages is the low capability of limiting the ablation area, thus large “ice balls” created by the probes during the treatment may cause fat necrosis and infection. Skin necrosis or pectoralis muscle necrosis hasbeen rarely reported, and instilling warm saline between the ice ball and skin surface during freezing helps in reducing the risk.21 Other minor adverse effects include breast pain, swelling, ecchymosis, and skin burns.1,8

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