CRYOABLATION OF BREAST CANCER IN COMPARISON WITH OTHER ABLATIVE TECHNIQUES

Few studies have compared cryoablation with other percutaneous ablative methods for breast cancer.1 Manenti et al compared radiofrequency ablation (40 patients) and cryoablation (40 patients) in the treatment of early breast cancer. All patients received sentinel lymph node biopsy. After 30–45 days from the ablation treatment, surgical resection of the tumor was scheduled. After 18-month follow-up, no local recurrences occurred. The authors observed complete necrosis in 75 patients (93.8%) and residual disease in 5 (6.2%). There was a good correlation between MRI volume and histologic samples. The conclusion of the study was that both percutaneous ablative methods achieved good clinical and cosmetic outcomes, but cryotherapy was the preferred method due to the analgesic effect of freezing with better patients compliance.34

Mauri et al assessed in a meta-analysis the technical success, technique efficacy, and complications of minimally invasive imaging-guided percutaneous ablation procedures for breast cancer. The study included 1156 patients with 1168 lesions from 45 studies. Cryoablation was used in 13% of patients, whereas radiofrequency the most used ablation method. Technique efficacy of cryoablation was 75%. General conclusions of the authors were that imaging-guided ablation techniques for breast cancer considered as a whole were 96% technically successful, but technique efficacy remains suboptimal. However, technique efficacy was significantly better in patients submitted to radiofrequency and cryoablation compared to laser, microwaves, and high intensity focused ultrasound.7


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IMAGING FOLLOW-UP AFTER CRYOABLATION TREATMENT

The extent of the ice ball caused by cryoablation can be recognized on US, CT scan, and MRI.8 However, timing and imaging methods of surveillance after breast cancer cryoablation remain to be better defined. In fact, early diagnosis of local recurrence after either surgical removal or ablation of the primary tumor is of paramount importance for disease-free survival, and perhaps for overall survival of patients with breast cancer. Contrast-enhanced MRI is a relatively new method in breast cancer detection and diagnosis, based on vascularization of tumor lesions. It has widely been used for planning surgical treatment in selected patients with invasive breast cancer and DCIS, and for assessing response to neoadjuvant systemic therapy.40,41 After cryoablation treatment, damaged cancer cells stay located in the treated area, thus MRI may be the most accurate image tool for evaluating responses to cryoablation.6,34,42 Manenti et al reported a good correlation between MRI volume and histological samples size in their series of 80 patients submitted to either radiofrequency ablation or cryoablation and surgical removal of the tumor.34 However, the role of MRI has been questioned by some authors. In the Z1072 trial, the negative predictive value of MRI was 81.2%.32 Poplack et al, in their retrospective study, observed that MRI was not useful to predict cryoablation results accurately, such as the detection of residual cancer and the recognition of benign cryoablation-related change.31

IMMUNOLOGIC EFFECTS OF CRYOABLATION

In the era of introduction of immunotherapy in the treatment of various malignancies, increasing interest has been directed toward the cryoablation-induced anti-tumor immune response, which may aid in tumor control and cure.3,21,43 The key point is that antigenic tissue remains in the breast after local ablation. Cryoablation of tumor lesions causes the coagulative necrosis of neoplastic cells. During the thawing phase, tumor cells within the iceball release in blood circulation intact tumor antigens, as well as other “danger signals”, such as nuclear proteins, proinflammatory cytokines, and HMGB1, a molecule that stimulates antitumor immunity response through interactions with Toll-like receptors. These signals act as a stimulus for the natural immune response by attracting macrophages, NK cells, and granulocytes. These cells, in addition, cause cytokines release and dendritic cells, the professional antigen-presenting cells, to reach the cryoablated tissue.44,45 There are many studies showing the clinical benefit of cancer antigens. In fact those antigens can stimulate the production of antitumor antibodies, cytotoxic T-cells and induce a vigorous cytokine response targeted toward malignant cells. Thus, tumor-derived self-antigens can be released into circulation. The most advantageous method for the immune system to identify these new circulating cryoablated self-antigens may be the enhanced immune response activation caused by blocking tumor checkpoints. Experimental and clinical studies demonstrated the complementary roles for cytotoxic T-lymphocyte-associated protein (CTLA-4) and PD-1 antagonists in influencing adaptive immunity. Combination immunotherapy followed by cryosurgery seems to provide a more targeted immune response to distant lesions.43,46

Various immunostimulation and immunomodulation pathways are activated by necrotic tissue damage-associated molecular products.20,43 Furthermore, increased interest has been raised regarding the possible synergic effects of cryoablation and systemic treatments.

In an experimental model of triple-negative breast cancer, Chandra et al tested cryoablation combined with Meriva (a lecithin delivery system of curcumin with improved bioavailability) founding that cryoablation delayed the development of pulmonary metastases on the short term, and that post-cryoablation Meriva administration was significantly better in delaying the development of pulmonary metastases, and affected survival on the long-term period.19

In a recent study, breast cryoablation was combined with immune therapy in 19 women scheduled for mastectomy in whom pre-operative tumor cryoablation, single-dose Ipilimumab, or both were administrated. Interestingly, in the patients who received the combination of cryoablation and Ipilimumab, synergistic antitumor immunity effects were observed.47

The clinical benefits of a combination of tumor cryoablation with natural killer cells therapy and Herceptin were studied from Liang et al. In 48 patients with HER2- overexpressing recurrent breast cancer, the three-therapy combination treatment resulted in reduced levels of circulating tumor cells, reduced tumor markers such as CEA and CA15-3, and significant prolongation of progression free survival.48 The synergetic effect of cryoablation and doxorubicin nanoparticles was assessed as effective in MCF-7 model, a widely studied epithelial cancer cell line derived from breast adenocarcinoma.49

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