CRYOABLATION FOR EARLY BREAST CANCER

Advances in systemic treatments and early diagnosis due to mammographic screening have led to a progressive de-escalation of breast cancer treatment towards less invasive forms of loco-regional interventions.22–24 Thus, breast-conserving surgery has become the treatment of choice for the majority of patients with early breast cancer. Recently, in line with ongoing researches in different fields of surgical oncology, nonoperative approaches such as percutaneous ablative techniques have been proposed such as possible alternative to surgery in selected patients with early breast cancer. Conventional surgical treatment of early breast cancer may have different complications or sequels which can prolong hospital stay, such as chronic pain, infection, hematoma, and seroma formation.24,25 Cryoablation treatment has some potential advantages over surgical operation. Because of the natural pain relieving effect of cold, cryoablation is usually painless. Therefore, it can be applied using either local anesthesia or peripheral nerve block, without general anesthesia. Since it is done percutaneously through a small needle hole, there is no incision, suture, and scar, and in general no deformation occurs in the breast with consequent aesthetics advantages. The patient can be discharged the same day of treatment and return to normal life almost immediately following the operation.18 Cryoablation for breast cancer represents an extension of its use in benign breast diseases. In fact, it was initially used in the treatment of fibroadenomas, with encouraging results in terms of ablation of the target lesions.26–29

In 2004, Sabel et al reported on 27 patients with invasive breast cancer who underwent US-guided cryoablation followed by surgical resection. Cryoablation destroyed successfully 100% of cancers ≤1.0 cm, whereas in patients with invasive ductal carcinomas between 1.0 and 1.5 cm, 100% success rate was obtained only for tumors without a significant ductal carcinoma in situ (DCIS) component. They concluded that cryoablation should be limited to invasive ductal carcinoma up to 1.5 cm in maximum diameter having <25% DCIS component in the core biopsy.30


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Poplack et al published in 2015 a retrospective study on 20 patients with invasive ductal carcinoma up to 15 mm, with limited or no DCIS who underwent US-guided cryoablation followed by surgical resection. They concluded that cryoablation was technically feasible and well tolerated by patients, although a clinical failure rate of 15% was observed. Interestingly, the authors highlighted that technical failures occurred when DCIS component was outside the cryoablation field.31

To date, the most important trial exploring the usefulness of cryoablation in the treatment of early breast cancer with curative intent was the level II trial ACOSOG Z1072. The primary endpoint was the rate of complete tumor ablation, defined as no remaining foci of either invasive or DCIS on pathological examination of the targeted lesion. Eighty-six patients with 87 unifocal invasive ductal carcinoma ≤2 cm underwent cryoablation and subsequent surgical resection of the target tumor within 28 days. Central pathologic review showed successful cryoablation in 75.9% of cancer lesions and residual invasive carcinoma and/or DCIS in 24.1%. There was 100% ablation in all tumors smaller than 1 cm. The authors concluded that technical adjustments and modifications in patient selection were needed to ameliorate cryoablation results in the non-surgical treatment of early breast cancer.32

Literature search reveals a high heterogeneity on this topic. Some studies enrolled a small number of patients at various stages of disease,18,33 in others surgical tumor removal was performed after cryoablation,31,34 and in others again percutaneous ablation was the only modality of treatment,6,35 thus reliable conclusions on the usefulness of cryoablation in the subgroup with early breast cancer could not be drawn.

The role of cryoablation in early breast cancer is under investigation in two ongoing trials in the US, the FROST (Freezing Instead of Removal Of Small Tumors) activated in 2016, and Ice3 (Cryoablation of Low Risk Small Breast Cancer) activated in 2014.36,37 Both studies seek to evaluate the role of cryoablation instead of surgery in women aged 50 years or older, having as primary endpoint assessment of 5-year local recurrence rate. Inclusion criteria in the FROST trial are: unifocal primary invasive breast carcinoma ≤1.5 cm in its greatest diameter, clinically node-negative, hormone receptor-positive, Her2 negative, with <25% intraductal component in the aggregate. Recruited patients will undergo US-guided cryoablation. After 6 months, an US-guided core biopsy of the cryoablated lesion will be performed, in order to confirm the absence of residual viable disease. Following cryoablation treatment, subjects will begin a minimum 5-year course of adjuvant hormonal therapy and serial mammography, US, and MRI. All subjects found to have residual or recurrent disease at follow-up image exams will undergo standard surgical resection.36 The ICE-3 trial has similar inclusion criteria: unifocal primary ducal invasive breast cancer ≤1.5 cm in greatest diameter, Nottingham grade 1–2, estrogen receptor-positive, progesterone receptor-positive, Her2 negative tumors. Final data collection for primary outcome measure are expected in December 2023.37

It is important to emphasize that at least 1 cm visible ice coverage beyond all tumor margins should be achieved when dealing with treatment of early breast cancer with curative attempt.18 In fact, the concept of obtaining “free margins” after breast conservation may be translated into “iced coverage beyond the tumor” after cryoablation and other ablative techniques. A 1-cm ice margin is generally considered as a conservative estimate of cytotoxic temperatures beyond the tumor.

To note, at present cryoablation has been reserved for treatment of patients with invasive ductal carcinoma. In fact, patients having pure DCIS or invasive ductal carcinoma with an extensive intraductal component cannot be considerate good candidates because those forms of breast cancer have indefinite margins at breast imaging (especially US and MRI) and may extend outside of the cryoablation-targeted ablation zone.15,30,38 Also, patients with invasive lobular carcinoma have generally been excluded because of frequent multicentricity and scarce correlation between tumor extension at preoperative imaging and final pathology examination.1

CRYOABLATION IN PATIENTS WITH METASTATIC DISEASE

The effectiveness of removing the primary tumor in patients presenting with metastatic breast cancer (Stage IV at diagnosis) remains under debate. The only recognized indication for salvage surgery exists for locally advanced tumors with poor or nil response after systemic pharmacologic treatment. In these cases, some forms of treatment of the primary tumor are required to avoiding bleeding and/or ulceration of the tumor mass.20 However, things are different for patients presenting at Stage IV and having nonpalpable or clinically indolent tumors who have stable metastatic disease. In those patients, lumpectomy or mastectomy may represent an unnecessary treatment, which also may have aesthetical and psychological consequences related to the surgical procedure. In addition, changes in breast tumor size can be used as a measure of chemosensitivity of the primary tumor.

However, there is a growing interest in percutaneous ablation in patients presenting at Stage IV, because it permits to obtain tumor necrosis without the inconveniences of surgical procedures (Figure 2). Pusceddu et al reported on 35 patients at stage IV with mean tumor size of 3 cm submitted to CT-guided cryoablation. Complete tumor necrosis was achieved in 85.7% and 100% of cases at 2-month and 6-month follow-up, respectively. No patient developed major complications, while minor side effects occurred in 30 patients (82%). After a mean follow-up of 46 months, 7 patients (20%) experienced local recurrences that were treated with redo cryoablation. The authors concluded that cryoablation of the primary tumor is safe and effective in the treatment of patients presenting with metastatic disease.20 In a recent report, Beji et al evaluated results of cryoablation in 17 patients with stable metastatic breast cancer. In 15 patients, a complete regression of the primary breast lesion without recurrence was observed, whereas local recurrence developed in 2 patients with tumors ≥40 mm. Both of them underwent a second cryotherapy.39 The possibility to redo cryoablation after local failure is one of the points of strength of that ablative method (Figure 3).


CRYOABLATION IN PATIENTS UNSUITABLE OF SURGERY

Cryoablation is nowadays widely used to treat breast cancer and other solid tumors, as this technique bears the major advantage of allowing accurate monitoring of iceball formation with different imaging modalities avoiding the use of contrast medium, i.e. unenhanced computed tomography. Although breast surgery can be usually safely performed in patients with relevant co-morbidities, there are some who are unsuitable for this approach due to general contra-indications (primarily cardiac or pulmonary insufficiency) or lack of consent for surgery (Figure 4). Cazzato et al carried out cryoablation in 23 elderly patients unsuitable for surgery, with median age of 86 years. After a median follow-up of 14.6 months, 5 patients developed local recurrence and 2 were successfully re-treated with cryoablation. At MRI follow-up, rates of primary complete local tumor control were 95.6%, 76.9%, 13.4%, and 9.4% at 3-, 12-, 18-, and 24-month, respectively.35

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