CLINICAL STUDY
Breast Cryoablation in Patients with Bone Metastatic Breast Cancer Claudio Pusceddu, MD, Barbara Sotgia, MD, Giovanni Amucano, MD, Rosa Maria Fele, MD, Sara Pilleri, MD, Giovanni Battista Meloni, MD, and Luca Melis, MD
ABSTRACT Purpose: To assess retrospectively the safety and feasibility of palliative breast cryoablation to treat primary breast tumors in patients with stage IV breast cancer. Materials and Methods: In 17 female patients (mean age ⫾ SD, 59 y ⫾ 13; range, 37–81 y) with 22 bone metastatic ductal invasive breast lesions (2.5 cm 1.6 cm ⫾ 1.4 1.1; range, 1.0 cm 0.5 cm to 6.7 cm 5.5 cm), 19 computed tomography (CT)–guided percutaneous cryoablation sessions were performed for treatment of primary breast tumors. All patients had radiologic evidence (contrast-enhanced CT or magnetic resonance imaging) of persistence or progression of the primary breast cancer despite systemic therapy. The radiologic outcome was evaluated with a mean follow-up period of 13 months (range, 3–31 mo). Treatment of skeletal metastases was unnecessary during the follow-up period. Results: All of the cryoablation sessions were completed and well tolerated. Complete regression of the disease was achieved in 15 (88%) patients 2 months after the cryoablation. Two (12%) patients underwent a second cryoablation treatment because of a minimal persistence of viable tumor (residual disease). No relapse of primary tumors was observed on breast imaging during the follow-up period. One patient (6%) developed a new lesion localized to the contralateral breast. Conclusions: These data suggest that palliative cryoablation of primary advanced breast cancer is a well-tolerated, feasible, and effective treatment option. Given the palliative effects of breast cryoablation demonstrated in this series, larger studies replicating these results are warranted.
ABBREVIATIONS HU = Hounsfield unit, ROI = region of interest
Metastatic breast cancer at diagnosis represents approximately 6%–10% of all new breast cancers. The prognosis for this group of patients is generally unfavorable. The 5-year relative survival rate is only 23%, although the overall survival is improving with the risk of death decreasing by 1%–2% each year (1,2). Metastatic breast cancer is considered an incurable disease, and the main treatment goal is palliation, with the aim of maintaining From the Division of Interventional Radiology (C.P.), Department of Oncological Radiology (B.S., G.A., R.M.F., L.M.), Ocological Hospital “A. Businco,” Regional Referral Center for Oncologic Diseases, Cagliari 09100, Italy; and Complex Operative Unit of Radiology (S.P., G.B.M.), Institute of Radiological Sciences, University of Sassari, Sassari, Italy. Received September 10, 2013; final revision received April 29, 2014; accepted May 2, 2014. Address correspondence to C.P.; E-mail: [email protected] None of the authors have identified a conflict of interest. & SIR, 2014 J Vasc Interv Radiol 2014; 25:1225–1232 http://dx.doi.org/10.1016/j.jvir.2014.05.001
or improving the quality of life and possibly improving survival. Palliative treatment options currently available to these patients include external-beam radiotherapy, chemotherapy and combined modalities, endocrine therapies, and biologic agents (1–3). Traditionally, the local treatment of stage IV breast cancer, through either surgery or radiotherapy, has been reserved for palliation of advanced local disease to prevent local complications (4,5). Population and institutional database reviews suggest that a significant percentage of women (approximately 40%–60%) receive surgery for their primary breast tumor as a component of therapy for stage IV disease (6–8). The biologic rationale for removing the primary breast tumor in cases of proven disease dissemination is debatable, but several observational studies have exhibited a higher survival rate among patients with stage IV breast cancer in whom the primary tumor is completely excised at the time of diagnosis (9–12). Ablative techniques, such as radiofrequency ablation,
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percutaneous cryoablation, interstitial laser ablation, and high-intensity focused ultrasound ablation, are being explored in the hope to avoid the need for surgery (13,14). Among these local ablative therapies, percutaneous cryoablation is a minimally invasive technique that has been proven to be a safe and effective technique for the treatment of local malignant disease in various organs (15–18). The aim of this retrospective review of our hospital’s database was to assess the technical safety, feasibility, and efficacy of computed tomography (CT)– guided percutaneous cryoablation to treat primary breast tumors in patients with metastatic breast cancer in the bone.
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carcinoma, tubular carcinoma), (b) presence of distant metastasis different from the skeletal metastasis (eg, liver and brain), (c) platelet count o 50 103/μL, and (d) unmanageable coagulation disorders. The patients were seen at our department approximately 2 weeks (range, 10–20 d) before cryoablation. Staging of the patients included chest radiography, bone scintigraphy, whole-body CT, breast magnetic resonance (MR) imaging, histologic confirmation of ductal invasive breast cancer, electrocardiogram, complete blood counts, and coagulation study. Patients taking anticoagulants and antiplatelet medications were advised to stop these therapies 2 days and 1 week before the procedure, respectively. Nonenhanced and contrast-enhanced MR imaging of the breast was considered the preferred imaging modality to assess the tumor characteristics (eg, size, intensity), but in 3 (18%) of 17 patients, evaluation of the primary breast cancer was conducted by enhanced and nonenhanced CT cross-sectional imaging because of patient claustrophobia. Treatment of skeletal metastases was not considered necessary unless the patients had painful metastasis or metastasis at high risk of fracture.
MATERIALS AND METHODS The indications, risks, and benefits of the cryoablation procedure were discussed with all the patients, and informed consent to perform this treatment was obtained. There were 17 female patients (mean age ⫾ SD, 59 y ⫾ 13; range, 37–81 y) with 22 bone metastatic ductal invasive breast lesions (2.5 cm 1.6 cm ⫾ 1.4 1.1 cm; range, 1.0 cm 0.5 cm to 6.7 cm 5.5 cm) who underwent 19 CT-guided percutaneous cryoablation sessions for the treatment of their primary breast tumors. All patients received the following systemic therapies: endocrine therapies in combination with bisphosphonates (n = 8; 47%), chemotherapy (n = 4; 24%), and anti–human epidermal growth receptor 2 therapy (n = 5; 29%). The characteristics of the patient population and tumor lesions are summarized in Table 1. The decision to perform breast cryoablation was made by the interventional radiologist after consultation with the patients and referring physicians. The patients were selected based on the following criteria: (a) stage IV ductal invasive breast cancer, (b) primary tumor located at a distance of at least 10 mm from the skin (to avoid skin burn), (c) clinical and radiologic evidence of persistence or progression of primary breast cancer despite systemic therapy at least 3 weeks before the ablation session, and (d) life expectancy 42 months. The criteria for exclusion were (a) histologic types of breast cancer different from the ductal type (eg, lobular
Imaging Techniques Breast MR imaging examinations were performed with the patients placed prone in a 1.5-tesla system (MAGNETOM Avanto; Siemens, Munich, Germany). A dedicated sensitivity-encoding breast coil was used for radiofrequency signal reception. Six dynamic acquisitions of T1-weighted three-dimensional fast low-angle shot sequences were performed. Between the first and the second acquisition, a pause of 20 seconds was used for the administration of 0.1 mL/kg gadobutrol (Gadovist; Schering AG, Berlin, Germany). Intensity/time enhancement curves were obtained by drawing a region of interest (ROI) around the areas of the lesions that showed the greatest degree of enhancement. Turbo inversion recovery magnitude sequences were acquired. Nonenhanced and enhanced CT images of the breast were acquired using a Somatom Sensation CT scanner (Siemens) with 3-mm collimation and 80–140 mA with the patient placed supine. Tumor measurements were obtained in three dimensions on the CT images, using
Table 1 . Baseline Characteristics of Patient Population and Tumor Lesions Data (n ¼ 17 Patients)
Characteristics Age (mean ⫾ SD)
59 y ⫾ 13 (range, 37–81 y)
Primitive tumor distribution
Unifocal lesions, 13 (76%)
Stage (TNM) T
Stage IV (100%) T1c ¼ 5 (29%)
T2 ¼ 9 (53%)
N0 ¼ 16 (94%)
N1 ¼ 1 (6%)†
N M Tumor size (mean ⫾ SD)
Multifocal lesions, 3 (18%) T3 ¼ 2 (12%)
— M1 ¼ 17 (100%)‡ 2.5 cm 1.6 cm ⫾ 1.4 1.1 (range, 1.0 cm 0.5 cm to 6.7 cm 5.5 cm)
*Right pectoralis major muscle infiltration. One ipsilateral axillary lymph node; maximum diameter ¼ 2.0 cm. ‡ M1: only skeletal metastases in all patients. †
Multicentric lesions, 1 (6%) T4 ¼ 1 (6%)*
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the widest tumor appearance in the transverse plane. The CT attenuation coefficient (density) of each tumor in Hounsfield units (HU) was obtained by drawing a ROI around the tumor, taking care to avoid the external margins of the lesion to minimize volume averaging with the surrounding tissue.
Breast Cryoablation Procedure All percutaneous cryoablation treatments were performed using CT guidance by a single board-certified interventional radiologist using an argon-based cryoablation unit (SeedNet; Galil Medical, Yokneam, Israel). To proceed to the correct positioning of the cryoprobes for breast cryoablation treatment, the tumor location, size, margin, and infiltration or fixation of adjacent anatomic structures were established during preoperative evaluations. The CT images were compared with the breast MR images acquired earlier. The different positioning of the patient and the compression effect determined by the supine versus prone position on CT and MR images (and the difference in modality) cause a minimal discrepancy in the size and location of the target lesions. After sterile preparation of the skin, 2–5 mL of 2% lidocaine was injected into the deep breast tissue, proximal to the tumor mass and along the expected course of the cryoprobes. After a small skin
incision with a scalpel (1–2 mm in length), one or more cryoprobes (1.47-mm diameter 17-gauge ISOTHERM IceRod and IceSphere needles; Galil Medical) were inserted into the targeted tumor under CT guidance, and one thermocouple for temperature monitoring was positioned. The breast cryoablation treatment is summarized in Table 2. The patients were maintained in a state of conscious sedation during the procedure (achieved with intravenous bolus of fentanyl citrate 50 μg), and vital signs (oximetry, blood pressure, and heart rate) were continuously monitored throughout the procedure. Warming bags were placed on the skin to avoid skin injury and to facilitate the aggressive ablation goal of extending visible ice 1 cm beyond all apparent tumor margins. In four patients (24%), the tumor lesions were multifocal and multicentric, and multiple cryoprobes were placed approximately 1.5 cm apart and o1 cm from all tumor margins according to established guidelines for generating cytotoxic isotherms in almost any tissue (19,20). For the relatively low heat load of breast tissue compared with internal organs, it was assumed that 1 cm of visible ice beyond all the tumor margins would generate cytotoxic temperatures (e.g., 401C) throughout the tumor (21). In the only patient (6%) with metastatic lymph node involvement, the ipsilateral axillary lymph node metastasis was treated in the same cryoablation session.
Table 2 . Summary of Breast Percutaneous Cryoablation Treatments Type of Cryoablation
No. Cryoablation Needles
Patient No.
Patient Age
Lesion Diameter (cm)
Needle
Used/No. Treatments
1
53
3.7 2.3
IceRod
3/1
2
60
2.0 1.0
IceRod
2/1
3 4
53 41
2.3 2.0 4.2 1.7
IceRod IceRod
2/1 2/1
5
52
5.1 3.0
IceRod
2/1
6 7
54 62
1.5 1.0 2.0 1.6
IceRod IceRod
2/1 2/1
8
79
3.0 2.9
IceRod
3/1
9 10
79 81
1.0 0.8 1.5 0.5
IceRod IceSphere
2/1 2/1
11
81
1.2 1.0
IceSphere
3/1
12 13
76 76
3.5 2.2 2.0 1.0
IceRod IceRod
2/1 2/1
14
61
6.7 5.5
IceRod
2/2
15 16
37 47
2.3 1.6 3.4 2.3
IceRod IceRod
2/1 3/2
17
59
2.8 1.6
IceRod
2/1
18 19
63 63
2.5 1.5 1.0 0.7
IceRod IceRod
2/1 1/1
20 21
63 64
1.0 0.8 1.5 1.0
IceRod IceRod
1/1 1/1
22
64
1.0 0.8
IceRod
1/1
23 24
47 61
1.9 1.0 1.5 0.5
IceSphere IceRod
2/1* 1/1*
*Second breast percutaneous cryoablation treatment.
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Cryoablation therapy consisted of two cycles each of 8 minutes of freezing, followed by a 4-minute active thawing phase and a 4-minute passive thawing phase for each of the cases. The passive thawing phase was used to maximize cell death (22). At the end of each phase of freezing, CT images were acquired in all patients to verify the presence of a homogeneous area of low density, owing to the iceball, which encompassed the tumor (Fig 1a–c). After the second phase of thawing, the probes and thermocouples were removed, without the need for suture.
MR Imaging and CT after the Procedure and Follow-up Evaluation After the end of the cryoablation procedures, breast CT images were acquired in all patients to detect early complications. The wounds were then properly treated by the application of a sterile patch, and the patients were transferred to the recovery room for observation. If stable and without complications, all patients were discharged 6–10 hours after the ablation and instructed to take an oral wide-spectrum prophylactic antibiotic therapy for 72 hours (clindamycin, 300 mg 2/d). After the breast cryoablation treatments and during the entire clinical and radiologic follow-up period, all the patients continued to receive their usual systemic therapies. The clinical outcome (cosmetic result) was evaluated at the end (time 0) and 1 month after (time I) the cryoablation procedures. The cosmetic assessment was based on the presence or absence of four parameters: appreciable nodular thickening on palpation, skin rash, bruising, and hyperpigmentation. The absence of such marks was interpreted as an optimal cosmetic result, and the presence of one or two signs was considered a good cosmetic result. Patients routinely underwent physical examination, chest x-ray, bone scintigraphy, and hepatic ultrasound at 3, 6, and 12 months in the first year after breast cryoablation treatments and every 6 months thereafter.
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The radiologic outcome was evaluated by breast MR imaging in 14 patients (82%) and by CT scan of the breast in the 3 claustrophobic patients (18%), with a time interval of 2 and 6 months after cryoablation treatment and yearly thereafter. The acquisition protocols used were the same as those used for the assessment of the characteristics of breast tumor lesions before the cryoablation procedure for both MR imaging and CT. At month 2, the complete loss of contrast enhancement on MR imaging or CT scans was considered a complete response to ablative therapy. At month 6, any changes in the contrast enhancement or any increases in the size of the treated lesions on breast MR imaging or CT scan were considered recurrences or disease progression. The timing of the radiologic outcome assessment was principally based on the evidence that early postoperative MR imaging or CT (up to at least 30 days) is hampered by strong enhancement of treated lesions as a result of inflammatory injury induced by cryoablation (22).
RESULTS All cryoablation sessions were successfully completed. CT scans performed at the end of the procedures demonstrated the extent of the iceball 1 cm beyond the limits of the tumor margins (safety margin). All procedures were well tolerated; all patients were discharged 6– 10 hours after treatment; and there were no procedurerelated complications, including complications related to the use of thermocouples, such as bleeding or skin necrosis. At the cosmetic assessment conducted immediately after the cryoablation procedures (time 0), skin rashes and appreciable nodular thickening were observed in 14 (82%) of 17 patients, nodular thickening alone was observed in 1 (6%) patient, and there were no skin symptoms in 2 (12%) patients. These marks were transient, and no intervention was required. The skin
Figure 1. A 37-year-old woman with stage IV primary breast cancer (patient no. 15 in Table 2). (a) Contrast-enhanced CT scan obtained immediately before cryoablation shows a primary neoplasm (arrow) located in the upper external quadrant of the left breast (diameter 2.3 cm 1.6 cm). (b) CT scan obtained during a cryoablation procedure using the mediastinal window setting shows two cryoablation needles (arrows) inserted into the primitive breast lesion. (c) CT scan obtained at the end of the cryoablation procedure shows the presence of a homogeneous area of low density because of the iceball (arrows), which encompassed the tumor.
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rashes and nodular thickening resolved spontaneously within 12 hours and 15–21 days, respectively. At 1 month after cryoablation (time I), the clinical evaluation showed an optimal cosmetic result in all patients. At baseline, the mean ⫾ SD breast tumor diameter was 2.5 cm 1.6 cm ⫾ 1.4 1.1 (range, 1.0 cm 0.5 cm to 6.7 cm 5.5 cm). On breast MR imaging, the time/signal intensity curves evaluated in 14 (82%) nonclaustrophobic patients were characterized as persistent, whereas the tumors evaluated by CT scan of the breast in 3 (18%) patients who were claustrophobic had a mean attenuation coefficient of 52 HU (range, 60–45 HU). Technical success (complete lack of enhancement and complete necrosis of the lesions) was achieved in 15 (88%) of 17 patients 2 months after the cryoablation treatments, including a patient with right pectoralis major muscle infiltration and a patient in whom the primary breast tumor and the ipsilateral axillary metastatic lymph node were treated in the same cryoablation session (Fig 2a–d). Among these 15 patients, 12 patients underwent breast MR imaging, and 3 patients underwent breast CT scan. On MR imaging, the time/signal intensity curves were characterized as washed-out, and on the CT images, the average HU was 8 (range, 10–5 HU). Minimal
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persistence of viable tumor (residual disease) was noted in 2 (12%) of 17 patients, possibly as a result of an incomplete overlap of the iceball. In these patients, the tumor diameters before cryoablation were 6.7 cm 5.5 cm and 3.4 cm 2.3 cm. On breast MR imaging after cryoablation, these two residual tumors had diameters of 1.9 cm 1.0 cm and 1.5 cm 0.5 cm, irregular margins, and a time/signal intensity curves characterized as persistent (Fig 3a–i). After cytologic confirmation of the breast tumor, these two patients underwent another cryoablation procedure. The complete response to this second cryoablation treatment was demonstrated by MR imaging 2 months later in both patients. This response was associated with an optimal cosmetic result immediately and 1 month after the second breast cryoablation procedure. At the 6-month radiologic follow-up evaluation, 1 (6%) of 17 patients developed a new breast lesion, which was located in the contralateral breast. A new cryoablation procedure was scheduled for this patient. Throughout the follow-up period, no recurrences or progression of primary tumors on breast imaging were observed. Only one patient (6%) died as a result of spread of the disease to the liver.
Figure 2. A 60-year-old woman with a primary breast cancer in the left breast (patient no. 2 in Table 2). (a) Axial contrast-enhanced T1weighted fat suppression MR image shows the primitive lesion in the external quadrant of the left breast before cryoablation (arrow). (b) Axial contrast enhanced T1-weighted fat suppression image obtained 2 months after cryoablation shows a large nonenhanced area, owing to necrosis, surrounded by a ring of enhanced tissue compatible with granulation tissue in the proliferative phase (arrows). (c) Acquisition turbo inversion recovery magnitude obtained 2 months after cryoablation shows that the treated lesion corresponds to a large central area (long arrow) attributable to a coagulative necrosis (characterized by marked T2 hyperintensity), surrounded by isointense adipose tissue and suggestive of steatonecrosis, delimited by an hyperintense T2 ring compatible with granulation tissue (short arrows). (d) T1 image (without suppression) obtained 2 months after cryoablation shows the same lesion characterized by a central nucleus that was hypointense on T1 imaging (coagulative necrosis) and surrounded by tissue necrosis with character-state (signal T1 similar to the adipose tissue), delimited by a ring of hypointensity (arrows).
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Figure 3. A 61-year-old woman with a primary breast cancer in the left breast (patient no. 14 in Table 2). (a–c) Images obtained before cryoablation. (a) Axial contrast-enhanced T1-weighted fat suppression image shows a large lesion with irregular margins involving the external quadrants of the left breast (arrows). The time/signal intensity curve obtained by drawing a ROI (b) onto the area of the lesion shows rapid, intense enhancement in the initial phase after contrast administration (corresponding to 80% of the maximum intensity) and a “plateau” in the late phase (c). (d–f) Images acquired 2 months after cryoablation. (d) Axial contrast-enhanced T1-weighted fat suppression image shows a 1.5 cm 0.5 cm lesion with irregular margins suspicious for persistence of vital tumor tissue (arrow). The time/signal intensity curve obtained by drawing a ROI (e) confirms this hypothesis, although the initial enhancement is less intense and faster than the enhancement observed in the time/signal intensity curve obtained before cryoablation (f). This lesion was treated with a further cryoablation procedure. (g–i) Images acquired 4 months after the last cryoablation procedure. (g) Axial contrast-enhanced T1weighted fat suppression image shows only a marginal enhancement of the lesion (arrows). The dynamic curve obtained by drawing a ROI (h) appears slow with a gradual and prolonged trend (type 1) suggestive of a benign lesion, compatible with granulation tissue (i). (Available in color online at www.jvir.org.)
DISCUSSION Metastatic breast cancer is a heterogeneous disease that has various different clinical scenarios, ranging from solitary metastatic lesions to diffuse and multiple organ involvement, with variable outcomes. In this scenario,
local therapy to treat primary breast tumors is not routinely recommended, and surgical procedures are reserved for patients who develop complications such as bleeding, ulceration, and infection at the primary tumor site (3–5). Several observational studies have shown a higher survival rate among patients with stage
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IV breast cancer in whom the primary tumor is completely excised at the time of the diagnosis (6–8). The biologic rationale for removing the primary tumor in cases of proven disease dissemination is still debatable, but many retrospective studies suggest the importance of local treatment of the primary tumor (9–12). Surgery of a primary breast tumor has reportedly been associated with a 39%–50% reduction in breast cancer mortality compared with women without surgical excision (11). The survival rate at 3 years and 5 years was 16%–26% for patients with positive margins and 27%–35% for patients with negative margins (12). Axillary dissection was not found to contribute significantly to survival (11,12). Because CT-guided percutaneous cryoablation has been proven to be a safe and feasible technique for the treatment of local malignant disease in other organs (15,16), use of this technique to manage primary breast tumors in patients without other treatment options is reasonable (14,23–25). Compared with other reports (23–25), one of the most important characteristics of our patient population is its homogeneity in terms of the type of breast tumor treated, histologic type, TNM classification, and type of distant metastases (Table 1). Regarding the cryoablation procedure, real-time imaging during the ablation procedure enhances the probability of complete tumor destruction, and for this reason, we prefer using CT guidance. It is well known that ultrasound is the most common method of monitoring the process of freezing, but ultrasound has some limitations caused by acoustic shadowing (22); ultrasound shows only the surface of the iceball, and the area behind the surface is not clearly visible, making accurate monitoring of that area difficult (26,27). CT guidance can be considered superior to ultrasound guidance for monitoring iceball formation during cryoablation procedures and for visualizing the entire iceball at the end of the cryoablation treatment. The main purpose of this retrospective review was to assess the technical safety, feasibility, and efficacy of CTguided percutaneous cryoablation in patients with stage IV bone metastatic ductal invasive breast cancer. Some publications in the literature show the feasibility of breast cryoablation for treating unifocal small ductal invasive breast tumors and breast cancer and lymph node axillary metastasis (23,24). Littrup et al (25) described the feasibility and efficacy of breast cryoablation without surgical excision in six patients with stage IV breast cancer. The present study differs from the study by Littrup et al (25) because only largediameter tumors (mean breast tumor diameter before treatment, 2.5 cm 1.4 cm vs 1.7 cm 1.2 cm) and primary ductal invasive stage IV breast cancer were treated (Table 1). Despite these differences, no local recurrences were observed during the follow-up period. All patients continued to receive their systemic therapies after cryoablation, and this therapy might have influenced the results observed here. Because persistence or
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progression of primary breast cancer was established in all patients already receiving this therapy, cryoablation empirically appears to have a positive influence. In this cohort, breast cryoablation treatments were not followed by surgical resection, which made it impossible to assess anatomopathologic changes, the excisional surgical specimen, and the extent and completeness of ablation. Because patients with metastatic breast cancer have a variable course of disease, some studies have evaluated the rate of locoregional recurrence of disease after surgery or after combined modalities (surgery and chemotherapy and radiotherapy). In the series by Morrogh et al (4), 41 (32%) of 128 patients who underwent breast local control surgery procedures presented with local recurrence of disease within a median time of 17.4 months. Huang et al (28) revealed 5-year and 10-year locoregional recurrence rates of 9% and 11%. The data from our patient population cannot be used as a direct comparison with surgical resection, but the results show that cryoablation can be considered a valuable treatment alternative to surgery. From the data we collected, an optimal cosmetic result was observed in all patients. This optimal cosmetic result could be related to the type of probes used. We selected thin cryoablation needles (17-gauge ¼ 1.47 mm), and the cryoprobes that were traditionally used in other studies were larger (eg, 11-gauge ¼ 3 mm; 14gauge ¼ 2.4 mm) (25,27). The treatment of skeletal metastases was unnecessary during the follow-up period. The treatment of skeletal metastases is mainly indicated for the palliation of pain and sites with a high risk for fracture (17); these situations were not encountered here. The present study has limitations. The patient sample size was small, and the study was retrospective. In this cohort, breast cryoablation treatments were not followed by surgical resection (23–25). Another limitation concerned the radiologic follow-up because both MR imaging and CT scan were used to assess the presence of residual tumor or local recurrences. In conclusion, this study suggests that palliative breast cryoablation is a well-tolerated, safe, feasible, and effective technique for treating primary breast tumors in patients with stage IV breast cancer. These results may introduce new methods of palliative treatment of primary tumors in these patients in combination with traditional therapy to limit the local progression of the disease.
REFERENCES 1. American Cancer Society. Cancer Facts & Figures 2010. Atlanta, GA: American Cancer Society; 2010. Available at: http://www.cancer.org/acs/ groups/content/@nho/documents/document/acspc-024113.pdf. Accessed June 10, 2013. 2. Coleman RE, Bertelli G, Beaumont T, et al. UK guidance document: treatment of metastatic breast cancer. Clin Oncol (R Coll Radiol) 2012; 24:169–176.
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3. Cardoso F, Fallowfield L, Costa A, et al. Locally recurrent or metastatic breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22(Suppl 6):vi25–vi30. 4. Morrogh M, Park A, Norton L, et al. Changing indications for surgery in patients with stage IV breast cancer: a current perspective. Cancer 2008; 112:1445–1454. 5. Morrow M, Goldstein L. Surgery of the primary tumor in metastatic breast cancer: closing the barn door after the horse has bolted? J Clin Oncol 2006; 24:2694–2696. 6. Andre F, Slimane K, Bachelot T, et al. Breast cancer with synchronous metastases: trends in survival during a 14-year period. J Clin Oncol 2004; 22:3302–3308. 7. Giordano SH, Buzdar AU, Smith TL, et al. Is breast cancer survival improving? Cancer 2004; 100:44–52. 8. Le Scodan R, Stevens D, Brain E, et al. Breast cancer with synchronous metastases: survival impact of exclusive locoregional radiotherapy. J Clin Oncol 2009; 27:1375–1381. 9. Ruiterkamp J, Ernst MF, van de Poll-Franse LV, et al. Surgical resection of the primary tumor is associated with improved survival in patients with distant metastatic breast cancer at diagnosis. Eur J Surg Oncol 2009; 35: 1146–1151. 10. Rao R, Feng L, Kuerer HM, et al. Timing of surgical intervention for the intact primary in stage IV breast cancer patients. Ann Surg Oncol 2008; 15:1696–1702. 11. Rapiti E, Verkooijen HM, Vlastos G, et al. Complete excision of primary breast tumor improves survival of patients with metastatic breast cancer at diagnosis. J Clin Oncol 2006; 24:2743–2749. 12. Khan SA, Stewart AK, Morrow M. Does aggressive local therapy improve survival in metastatic breast cancer? Surgery 2002; 132: 620–627. 13. Simpson JS, Ma G, Holloway CM. Imaging technologies in breast diagnosis and surgical treatment. Minerva Chir 2011; 66:455–468. 14. Zhao Z, Wu F. Minimally-invasive thermal ablation of early-stage breast cancer: a systemic review. Eur J Surg Oncol 2010; 36:1149–1155. 15. Wang H, Littrup PJ, Duan Y, et al. Thoracic masses treated with percutaneous cryotherapy: initial experience with more than 200 procedures. Radiology 2005; 235:289–298.
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16. Atwell TD, Farrell MA, Leibovich BC, et al. Percutaneous renal cryoablation: experience treating 115 tumors. J Urol 2008; 179:2136–2140. 17. McMenomy BP, Kurup AN, Johnson GB, et al. Percutaneous cryoablation of musculoskeletal oligometastatic disease for complete remission. J Vasc Interv Radiol 2013; 24:207–213. 18. Littrup PJ, Bang HJ, Currier BP. Soft-tissue cryoablation in diffuse locations: feasibility and intermediate term outcomes. J Vasc Interv Radiol 2013; 24:1817–1825. 19. Rewcastle JC, Sandison GA, Muldrew K, et al. A model for the time dependent three-dimensional thermal distribution within iceballs surrounding multiple cryoprobes. Med Phys 2001; 28:1125–1137. 20. Permpongkosol S, Nicol TL, Khurana H, et al. Thermal maps around two adjacent cryoprobes creating overlapping ablations in porcine liver, lung and kidney. J Vasc Interv Radiol 2007; 18:283–287. 21. Littrup PJ, Jallad B, Vorugu V, et al. Lethal isotherms of cryoablation in a phantom study: effects of heat load, probe size and number. J Vasc Interv Radiol 2009; 20:1343–1351. 22. Gage AA, Baust JM, Baust JG. Experimental cryosurgery investigations in vivo. Cryobiology 2009; 59:229–243. 23. Manenti G, Perretta T, Gaspari E, et al. Percutaneous local ablation of unifocal subclinical breast cancer: clinical experience and preliminary results of cryotherapy. Eur Radiol 2011; 21:2344–2353. 24. Pusceddu C, Capobianco G, Meloni F, et al. CT-guided cryoablation of both breast cancer and lymph node axillary metastasis. Eur J Gynaecol Oncol 2011; 32:224–225. 25. Littrup PJ, Jallad B, Chandiwala-Mody P, et al. Cryotherapy for breast cancer: a feasibility study without excision. J Vasc Interv Radiol 2009; 20:1329–1341. 26. Pfleiderer SO, Marx C, Camara O, et al. Ultrasound-guided, percutaneous cryotherapy of small (o or ¼ 15 mm) breast cancers. Invest Radiol 2005; 40:472–477. 27. Pfleiderer SO, Freesmeyer MG, Marx C, et al. Cryotherapy of breast cancer under ultrasound guidance: initial results and limitations. Eur Radiol 2002; 12:3009–3014. 28. Huang EH, Tucker SL, Strom EA, et al. Predictors of locoregional recurrence in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy, mastectomy and radiotherapy. Int J Oncol Biol Phys 2005; 62:351–357.
Breast Cryoablation in Patients with Bone Metastatic Breast Cancer Claudio Pusceddu, MD, Barbara Sotgia, MD, Giovanni Amucano, MD, Rosa Maria Fele, MD, Sara Pilleri, MD, Giovanni Battista Meloni, MD, and Luca Melis, MD
ABSTRACT Purpose: To assess retrospectively the safety and feasibility of palliative breast cryoablation to treat primary breast tumors in patients with stage IV breast cancer. Materials and Methods: In 17 female patients (mean age ⫾ SD, 59 y ⫾ 13; range, 37–81 y) with 22 bone metastatic ductal invasive breast lesions (2.5 cm 1.6 cm ⫾ 1.4 1.1; range, 1.0 cm 0.5 cm to 6.7 cm 5.5 cm), 19 computed tomography (CT)–guided percutaneous cryoablation sessions were performed for treatment of primary breast tumors. All patients had radiologic evidence (contrast-enhanced CT or magnetic resonance imaging) of persistence or progression of the primary breast cancer despite systemic therapy. The radiologic outcome was evaluated with a mean follow-up period of 13 months (range, 3–31 mo). Treatment of skeletal metastases was unnecessary during the follow-up period. Results: All of the cryoablation sessions were completed and well tolerated. Complete regression of the disease was achieved in 15 (88%) patients 2 months after the cryoablation. Two (12%) patients underwent a second cryoablation treatment because of a minimal persistence of viable tumor (residual disease). No relapse of primary tumors was observed on breast imaging during the follow-up period. One patient (6%) developed a new lesion localized to the contralateral breast. Conclusions: These data suggest that palliative cryoablation of primary advanced breast cancer is a well-tolerated, feasible, and effective treatment option. Given the palliative effects of breast cryoablation demonstrated in this series, larger studies replicating these results are warranted.
ABBREVIATIONS HU = Hounsfield unit, ROI = region of interest
Metastatic breast cancer at diagnosis represents approximately 6%–10% of all new breast cancers. The prognosis for this group of patients is generally unfavorable. The 5-year relative survival rate is only 23%, although the overall survival is improving with the risk of death decreasing by 1%–2% each year (1,2). Metastatic breast cancer is considered an incurable disease, and the main treatment goal is palliation, with the aim of maintaining From the Division of Interventional Radiology (C.P.), Department of Oncological Radiology (B.S., G.A., R.M.F., L.M.), Ocological Hospital “A. Businco,” Regional Referral Center for Oncologic Diseases, Cagliari 09100, Italy; and Complex Operative Unit of Radiology (S.P., G.B.M.), Institute of Radiological Sciences, University of Sassari, Sassari, Italy. Received September 10, 2013; final revision received April 29, 2014; accepted May 2, 2014. Address correspondence to C.P.; E-mail: [email protected] None of the authors have identified a conflict of interest. & SIR, 2014 J Vasc Interv Radiol 2014; 25:1225–1232 http://dx.doi.org/10.1016/j.jvir.2014.05.001
or improving the quality of life and possibly improving survival. Palliative treatment options currently available to these patients include external-beam radiotherapy, chemotherapy and combined modalities, endocrine therapies, and biologic agents (1–3). Traditionally, the local treatment of stage IV breast cancer, through either surgery or radiotherapy, has been reserved for palliation of advanced local disease to prevent local complications (4,5). Population and institutional database reviews suggest that a significant percentage of women (approximately 40%–60%) receive surgery for their primary breast tumor as a component of therapy for stage IV disease (6–8). The biologic rationale for removing the primary breast tumor in cases of proven disease dissemination is debatable, but several observational studies have exhibited a higher survival rate among patients with stage IV breast cancer in whom the primary tumor is completely excised at the time of diagnosis (9–12). Ablative techniques, such as radiofrequency ablation,
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percutaneous cryoablation, interstitial laser ablation, and high-intensity focused ultrasound ablation, are being explored in the hope to avoid the need for surgery (13,14). Among these local ablative therapies, percutaneous cryoablation is a minimally invasive technique that has been proven to be a safe and effective technique for the treatment of local malignant disease in various organs (15–18). The aim of this retrospective review of our hospital’s database was to assess the technical safety, feasibility, and efficacy of computed tomography (CT)– guided percutaneous cryoablation to treat primary breast tumors in patients with metastatic breast cancer in the bone.
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carcinoma, tubular carcinoma), (b) presence of distant metastasis different from the skeletal metastasis (eg, liver and brain), (c) platelet count o 50 103/μL, and (d) unmanageable coagulation disorders. The patients were seen at our department approximately 2 weeks (range, 10–20 d) before cryoablation. Staging of the patients included chest radiography, bone scintigraphy, whole-body CT, breast magnetic resonance (MR) imaging, histologic confirmation of ductal invasive breast cancer, electrocardiogram, complete blood counts, and coagulation study. Patients taking anticoagulants and antiplatelet medications were advised to stop these therapies 2 days and 1 week before the procedure, respectively. Nonenhanced and contrast-enhanced MR imaging of the breast was considered the preferred imaging modality to assess the tumor characteristics (eg, size, intensity), but in 3 (18%) of 17 patients, evaluation of the primary breast cancer was conducted by enhanced and nonenhanced CT cross-sectional imaging because of patient claustrophobia. Treatment of skeletal metastases was not considered necessary unless the patients had painful metastasis or metastasis at high risk of fracture.
MATERIALS AND METHODS The indications, risks, and benefits of the cryoablation procedure were discussed with all the patients, and informed consent to perform this treatment was obtained. There were 17 female patients (mean age ⫾ SD, 59 y ⫾ 13; range, 37–81 y) with 22 bone metastatic ductal invasive breast lesions (2.5 cm 1.6 cm ⫾ 1.4 1.1 cm; range, 1.0 cm 0.5 cm to 6.7 cm 5.5 cm) who underwent 19 CT-guided percutaneous cryoablation sessions for the treatment of their primary breast tumors. All patients received the following systemic therapies: endocrine therapies in combination with bisphosphonates (n = 8; 47%), chemotherapy (n = 4; 24%), and anti–human epidermal growth receptor 2 therapy (n = 5; 29%). The characteristics of the patient population and tumor lesions are summarized in Table 1. The decision to perform breast cryoablation was made by the interventional radiologist after consultation with the patients and referring physicians. The patients were selected based on the following criteria: (a) stage IV ductal invasive breast cancer, (b) primary tumor located at a distance of at least 10 mm from the skin (to avoid skin burn), (c) clinical and radiologic evidence of persistence or progression of primary breast cancer despite systemic therapy at least 3 weeks before the ablation session, and (d) life expectancy 42 months. The criteria for exclusion were (a) histologic types of breast cancer different from the ductal type (eg, lobular
Imaging Techniques Breast MR imaging examinations were performed with the patients placed prone in a 1.5-tesla system (MAGNETOM Avanto; Siemens, Munich, Germany). A dedicated sensitivity-encoding breast coil was used for radiofrequency signal reception. Six dynamic acquisitions of T1-weighted three-dimensional fast low-angle shot sequences were performed. Between the first and the second acquisition, a pause of 20 seconds was used for the administration of 0.1 mL/kg gadobutrol (Gadovist; Schering AG, Berlin, Germany). Intensity/time enhancement curves were obtained by drawing a region of interest (ROI) around the areas of the lesions that showed the greatest degree of enhancement. Turbo inversion recovery magnitude sequences were acquired. Nonenhanced and enhanced CT images of the breast were acquired using a Somatom Sensation CT scanner (Siemens) with 3-mm collimation and 80–140 mA with the patient placed supine. Tumor measurements were obtained in three dimensions on the CT images, using
Table 1 . Baseline Characteristics of Patient Population and Tumor Lesions Data (n ¼ 17 Patients)
Characteristics Age (mean ⫾ SD)
59 y ⫾ 13 (range, 37–81 y)
Primitive tumor distribution
Unifocal lesions, 13 (76%)
Stage (TNM) T
Stage IV (100%) T1c ¼ 5 (29%)
T2 ¼ 9 (53%)
N0 ¼ 16 (94%)
N1 ¼ 1 (6%)†
N M Tumor size (mean ⫾ SD)
Multifocal lesions, 3 (18%) T3 ¼ 2 (12%)
— M1 ¼ 17 (100%)‡ 2.5 cm 1.6 cm ⫾ 1.4 1.1 (range, 1.0 cm 0.5 cm to 6.7 cm 5.5 cm)
*Right pectoralis major muscle infiltration. One ipsilateral axillary lymph node; maximum diameter ¼ 2.0 cm. ‡ M1: only skeletal metastases in all patients. †
Multicentric lesions, 1 (6%) T4 ¼ 1 (6%)*
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the widest tumor appearance in the transverse plane. The CT attenuation coefficient (density) of each tumor in Hounsfield units (HU) was obtained by drawing a ROI around the tumor, taking care to avoid the external margins of the lesion to minimize volume averaging with the surrounding tissue.
Breast Cryoablation Procedure All percutaneous cryoablation treatments were performed using CT guidance by a single board-certified interventional radiologist using an argon-based cryoablation unit (SeedNet; Galil Medical, Yokneam, Israel). To proceed to the correct positioning of the cryoprobes for breast cryoablation treatment, the tumor location, size, margin, and infiltration or fixation of adjacent anatomic structures were established during preoperative evaluations. The CT images were compared with the breast MR images acquired earlier. The different positioning of the patient and the compression effect determined by the supine versus prone position on CT and MR images (and the difference in modality) cause a minimal discrepancy in the size and location of the target lesions. After sterile preparation of the skin, 2–5 mL of 2% lidocaine was injected into the deep breast tissue, proximal to the tumor mass and along the expected course of the cryoprobes. After a small skin
incision with a scalpel (1–2 mm in length), one or more cryoprobes (1.47-mm diameter 17-gauge ISOTHERM IceRod and IceSphere needles; Galil Medical) were inserted into the targeted tumor under CT guidance, and one thermocouple for temperature monitoring was positioned. The breast cryoablation treatment is summarized in Table 2. The patients were maintained in a state of conscious sedation during the procedure (achieved with intravenous bolus of fentanyl citrate 50 μg), and vital signs (oximetry, blood pressure, and heart rate) were continuously monitored throughout the procedure. Warming bags were placed on the skin to avoid skin injury and to facilitate the aggressive ablation goal of extending visible ice 1 cm beyond all apparent tumor margins. In four patients (24%), the tumor lesions were multifocal and multicentric, and multiple cryoprobes were placed approximately 1.5 cm apart and o1 cm from all tumor margins according to established guidelines for generating cytotoxic isotherms in almost any tissue (19,20). For the relatively low heat load of breast tissue compared with internal organs, it was assumed that 1 cm of visible ice beyond all the tumor margins would generate cytotoxic temperatures (e.g., 401C) throughout the tumor (21). In the only patient (6%) with metastatic lymph node involvement, the ipsilateral axillary lymph node metastasis was treated in the same cryoablation session.
Table 2 . Summary of Breast Percutaneous Cryoablation Treatments Type of Cryoablation
No. Cryoablation Needles
Patient No.
Patient Age
Lesion Diameter (cm)
Needle
Used/No. Treatments
1
53
3.7 2.3
IceRod
3/1
2
60
2.0 1.0
IceRod
2/1
3 4
53 41
2.3 2.0 4.2 1.7
IceRod IceRod
2/1 2/1
5
52
5.1 3.0
IceRod
2/1
6 7
54 62
1.5 1.0 2.0 1.6
IceRod IceRod
2/1 2/1
8
79
3.0 2.9
IceRod
3/1
9 10
79 81
1.0 0.8 1.5 0.5
IceRod IceSphere
2/1 2/1
11
81
1.2 1.0
IceSphere
3/1
12 13
76 76
3.5 2.2 2.0 1.0
IceRod IceRod
2/1 2/1
14
61
6.7 5.5
IceRod
2/2
15 16
37 47
2.3 1.6 3.4 2.3
IceRod IceRod
2/1 3/2
17
59
2.8 1.6
IceRod
2/1
18 19
63 63
2.5 1.5 1.0 0.7
IceRod IceRod
2/1 1/1
20 21
63 64
1.0 0.8 1.5 1.0
IceRod IceRod
1/1 1/1
22
64
1.0 0.8
IceRod
1/1
23 24
47 61
1.9 1.0 1.5 0.5
IceSphere IceRod
2/1* 1/1*
*Second breast percutaneous cryoablation treatment.
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Cryoablation therapy consisted of two cycles each of 8 minutes of freezing, followed by a 4-minute active thawing phase and a 4-minute passive thawing phase for each of the cases. The passive thawing phase was used to maximize cell death (22). At the end of each phase of freezing, CT images were acquired in all patients to verify the presence of a homogeneous area of low density, owing to the iceball, which encompassed the tumor (Fig 1a–c). After the second phase of thawing, the probes and thermocouples were removed, without the need for suture.
MR Imaging and CT after the Procedure and Follow-up Evaluation After the end of the cryoablation procedures, breast CT images were acquired in all patients to detect early complications. The wounds were then properly treated by the application of a sterile patch, and the patients were transferred to the recovery room for observation. If stable and without complications, all patients were discharged 6–10 hours after the ablation and instructed to take an oral wide-spectrum prophylactic antibiotic therapy for 72 hours (clindamycin, 300 mg 2/d). After the breast cryoablation treatments and during the entire clinical and radiologic follow-up period, all the patients continued to receive their usual systemic therapies. The clinical outcome (cosmetic result) was evaluated at the end (time 0) and 1 month after (time I) the cryoablation procedures. The cosmetic assessment was based on the presence or absence of four parameters: appreciable nodular thickening on palpation, skin rash, bruising, and hyperpigmentation. The absence of such marks was interpreted as an optimal cosmetic result, and the presence of one or two signs was considered a good cosmetic result. Patients routinely underwent physical examination, chest x-ray, bone scintigraphy, and hepatic ultrasound at 3, 6, and 12 months in the first year after breast cryoablation treatments and every 6 months thereafter.
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The radiologic outcome was evaluated by breast MR imaging in 14 patients (82%) and by CT scan of the breast in the 3 claustrophobic patients (18%), with a time interval of 2 and 6 months after cryoablation treatment and yearly thereafter. The acquisition protocols used were the same as those used for the assessment of the characteristics of breast tumor lesions before the cryoablation procedure for both MR imaging and CT. At month 2, the complete loss of contrast enhancement on MR imaging or CT scans was considered a complete response to ablative therapy. At month 6, any changes in the contrast enhancement or any increases in the size of the treated lesions on breast MR imaging or CT scan were considered recurrences or disease progression. The timing of the radiologic outcome assessment was principally based on the evidence that early postoperative MR imaging or CT (up to at least 30 days) is hampered by strong enhancement of treated lesions as a result of inflammatory injury induced by cryoablation (22).
RESULTS All cryoablation sessions were successfully completed. CT scans performed at the end of the procedures demonstrated the extent of the iceball 1 cm beyond the limits of the tumor margins (safety margin). All procedures were well tolerated; all patients were discharged 6– 10 hours after treatment; and there were no procedurerelated complications, including complications related to the use of thermocouples, such as bleeding or skin necrosis. At the cosmetic assessment conducted immediately after the cryoablation procedures (time 0), skin rashes and appreciable nodular thickening were observed in 14 (82%) of 17 patients, nodular thickening alone was observed in 1 (6%) patient, and there were no skin symptoms in 2 (12%) patients. These marks were transient, and no intervention was required. The skin
Figure 1. A 37-year-old woman with stage IV primary breast cancer (patient no. 15 in Table 2). (a) Contrast-enhanced CT scan obtained immediately before cryoablation shows a primary neoplasm (arrow) located in the upper external quadrant of the left breast (diameter 2.3 cm 1.6 cm). (b) CT scan obtained during a cryoablation procedure using the mediastinal window setting shows two cryoablation needles (arrows) inserted into the primitive breast lesion. (c) CT scan obtained at the end of the cryoablation procedure shows the presence of a homogeneous area of low density because of the iceball (arrows), which encompassed the tumor.
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rashes and nodular thickening resolved spontaneously within 12 hours and 15–21 days, respectively. At 1 month after cryoablation (time I), the clinical evaluation showed an optimal cosmetic result in all patients. At baseline, the mean ⫾ SD breast tumor diameter was 2.5 cm 1.6 cm ⫾ 1.4 1.1 (range, 1.0 cm 0.5 cm to 6.7 cm 5.5 cm). On breast MR imaging, the time/signal intensity curves evaluated in 14 (82%) nonclaustrophobic patients were characterized as persistent, whereas the tumors evaluated by CT scan of the breast in 3 (18%) patients who were claustrophobic had a mean attenuation coefficient of 52 HU (range, 60–45 HU). Technical success (complete lack of enhancement and complete necrosis of the lesions) was achieved in 15 (88%) of 17 patients 2 months after the cryoablation treatments, including a patient with right pectoralis major muscle infiltration and a patient in whom the primary breast tumor and the ipsilateral axillary metastatic lymph node were treated in the same cryoablation session (Fig 2a–d). Among these 15 patients, 12 patients underwent breast MR imaging, and 3 patients underwent breast CT scan. On MR imaging, the time/signal intensity curves were characterized as washed-out, and on the CT images, the average HU was 8 (range, 10–5 HU). Minimal
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persistence of viable tumor (residual disease) was noted in 2 (12%) of 17 patients, possibly as a result of an incomplete overlap of the iceball. In these patients, the tumor diameters before cryoablation were 6.7 cm 5.5 cm and 3.4 cm 2.3 cm. On breast MR imaging after cryoablation, these two residual tumors had diameters of 1.9 cm 1.0 cm and 1.5 cm 0.5 cm, irregular margins, and a time/signal intensity curves characterized as persistent (Fig 3a–i). After cytologic confirmation of the breast tumor, these two patients underwent another cryoablation procedure. The complete response to this second cryoablation treatment was demonstrated by MR imaging 2 months later in both patients. This response was associated with an optimal cosmetic result immediately and 1 month after the second breast cryoablation procedure. At the 6-month radiologic follow-up evaluation, 1 (6%) of 17 patients developed a new breast lesion, which was located in the contralateral breast. A new cryoablation procedure was scheduled for this patient. Throughout the follow-up period, no recurrences or progression of primary tumors on breast imaging were observed. Only one patient (6%) died as a result of spread of the disease to the liver.
Figure 2. A 60-year-old woman with a primary breast cancer in the left breast (patient no. 2 in Table 2). (a) Axial contrast-enhanced T1weighted fat suppression MR image shows the primitive lesion in the external quadrant of the left breast before cryoablation (arrow). (b) Axial contrast enhanced T1-weighted fat suppression image obtained 2 months after cryoablation shows a large nonenhanced area, owing to necrosis, surrounded by a ring of enhanced tissue compatible with granulation tissue in the proliferative phase (arrows). (c) Acquisition turbo inversion recovery magnitude obtained 2 months after cryoablation shows that the treated lesion corresponds to a large central area (long arrow) attributable to a coagulative necrosis (characterized by marked T2 hyperintensity), surrounded by isointense adipose tissue and suggestive of steatonecrosis, delimited by an hyperintense T2 ring compatible with granulation tissue (short arrows). (d) T1 image (without suppression) obtained 2 months after cryoablation shows the same lesion characterized by a central nucleus that was hypointense on T1 imaging (coagulative necrosis) and surrounded by tissue necrosis with character-state (signal T1 similar to the adipose tissue), delimited by a ring of hypointensity (arrows).
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Figure 3. A 61-year-old woman with a primary breast cancer in the left breast (patient no. 14 in Table 2). (a–c) Images obtained before cryoablation. (a) Axial contrast-enhanced T1-weighted fat suppression image shows a large lesion with irregular margins involving the external quadrants of the left breast (arrows). The time/signal intensity curve obtained by drawing a ROI (b) onto the area of the lesion shows rapid, intense enhancement in the initial phase after contrast administration (corresponding to 80% of the maximum intensity) and a “plateau” in the late phase (c). (d–f) Images acquired 2 months after cryoablation. (d) Axial contrast-enhanced T1-weighted fat suppression image shows a 1.5 cm 0.5 cm lesion with irregular margins suspicious for persistence of vital tumor tissue (arrow). The time/signal intensity curve obtained by drawing a ROI (e) confirms this hypothesis, although the initial enhancement is less intense and faster than the enhancement observed in the time/signal intensity curve obtained before cryoablation (f). This lesion was treated with a further cryoablation procedure. (g–i) Images acquired 4 months after the last cryoablation procedure. (g) Axial contrast-enhanced T1weighted fat suppression image shows only a marginal enhancement of the lesion (arrows). The dynamic curve obtained by drawing a ROI (h) appears slow with a gradual and prolonged trend (type 1) suggestive of a benign lesion, compatible with granulation tissue (i). (Available in color online at www.jvir.org.)
DISCUSSION Metastatic breast cancer is a heterogeneous disease that has various different clinical scenarios, ranging from solitary metastatic lesions to diffuse and multiple organ involvement, with variable outcomes. In this scenario,
local therapy to treat primary breast tumors is not routinely recommended, and surgical procedures are reserved for patients who develop complications such as bleeding, ulceration, and infection at the primary tumor site (3–5). Several observational studies have shown a higher survival rate among patients with stage
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IV breast cancer in whom the primary tumor is completely excised at the time of the diagnosis (6–8). The biologic rationale for removing the primary tumor in cases of proven disease dissemination is still debatable, but many retrospective studies suggest the importance of local treatment of the primary tumor (9–12). Surgery of a primary breast tumor has reportedly been associated with a 39%–50% reduction in breast cancer mortality compared with women without surgical excision (11). The survival rate at 3 years and 5 years was 16%–26% for patients with positive margins and 27%–35% for patients with negative margins (12). Axillary dissection was not found to contribute significantly to survival (11,12). Because CT-guided percutaneous cryoablation has been proven to be a safe and feasible technique for the treatment of local malignant disease in other organs (15,16), use of this technique to manage primary breast tumors in patients without other treatment options is reasonable (14,23–25). Compared with other reports (23–25), one of the most important characteristics of our patient population is its homogeneity in terms of the type of breast tumor treated, histologic type, TNM classification, and type of distant metastases (Table 1). Regarding the cryoablation procedure, real-time imaging during the ablation procedure enhances the probability of complete tumor destruction, and for this reason, we prefer using CT guidance. It is well known that ultrasound is the most common method of monitoring the process of freezing, but ultrasound has some limitations caused by acoustic shadowing (22); ultrasound shows only the surface of the iceball, and the area behind the surface is not clearly visible, making accurate monitoring of that area difficult (26,27). CT guidance can be considered superior to ultrasound guidance for monitoring iceball formation during cryoablation procedures and for visualizing the entire iceball at the end of the cryoablation treatment. The main purpose of this retrospective review was to assess the technical safety, feasibility, and efficacy of CTguided percutaneous cryoablation in patients with stage IV bone metastatic ductal invasive breast cancer. Some publications in the literature show the feasibility of breast cryoablation for treating unifocal small ductal invasive breast tumors and breast cancer and lymph node axillary metastasis (23,24). Littrup et al (25) described the feasibility and efficacy of breast cryoablation without surgical excision in six patients with stage IV breast cancer. The present study differs from the study by Littrup et al (25) because only largediameter tumors (mean breast tumor diameter before treatment, 2.5 cm 1.4 cm vs 1.7 cm 1.2 cm) and primary ductal invasive stage IV breast cancer were treated (Table 1). Despite these differences, no local recurrences were observed during the follow-up period. All patients continued to receive their systemic therapies after cryoablation, and this therapy might have influenced the results observed here. Because persistence or
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progression of primary breast cancer was established in all patients already receiving this therapy, cryoablation empirically appears to have a positive influence. In this cohort, breast cryoablation treatments were not followed by surgical resection, which made it impossible to assess anatomopathologic changes, the excisional surgical specimen, and the extent and completeness of ablation. Because patients with metastatic breast cancer have a variable course of disease, some studies have evaluated the rate of locoregional recurrence of disease after surgery or after combined modalities (surgery and chemotherapy and radiotherapy). In the series by Morrogh et al (4), 41 (32%) of 128 patients who underwent breast local control surgery procedures presented with local recurrence of disease within a median time of 17.4 months. Huang et al (28) revealed 5-year and 10-year locoregional recurrence rates of 9% and 11%. The data from our patient population cannot be used as a direct comparison with surgical resection, but the results show that cryoablation can be considered a valuable treatment alternative to surgery. From the data we collected, an optimal cosmetic result was observed in all patients. This optimal cosmetic result could be related to the type of probes used. We selected thin cryoablation needles (17-gauge ¼ 1.47 mm), and the cryoprobes that were traditionally used in other studies were larger (eg, 11-gauge ¼ 3 mm; 14gauge ¼ 2.4 mm) (25,27). The treatment of skeletal metastases was unnecessary during the follow-up period. The treatment of skeletal metastases is mainly indicated for the palliation of pain and sites with a high risk for fracture (17); these situations were not encountered here. The present study has limitations. The patient sample size was small, and the study was retrospective. In this cohort, breast cryoablation treatments were not followed by surgical resection (23–25). Another limitation concerned the radiologic follow-up because both MR imaging and CT scan were used to assess the presence of residual tumor or local recurrences. In conclusion, this study suggests that palliative breast cryoablation is a well-tolerated, safe, feasible, and effective technique for treating primary breast tumors in patients with stage IV breast cancer. These results may introduce new methods of palliative treatment of primary tumors in these patients in combination with traditional therapy to limit the local progression of the disease.
REFERENCES 1. American Cancer Society. Cancer Facts & Figures 2010. Atlanta, GA: American Cancer Society; 2010. Available at: http://www.cancer.org/acs/ groups/content/@nho/documents/document/acspc-024113.pdf. Accessed June 10, 2013. 2. Coleman RE, Bertelli G, Beaumont T, et al. UK guidance document: treatment of metastatic breast cancer. Clin Oncol (R Coll Radiol) 2012; 24:169–176.
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3. Cardoso F, Fallowfield L, Costa A, et al. Locally recurrent or metastatic breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22(Suppl 6):vi25–vi30. 4. Morrogh M, Park A, Norton L, et al. Changing indications for surgery in patients with stage IV breast cancer: a current perspective. Cancer 2008; 112:1445–1454. 5. Morrow M, Goldstein L. Surgery of the primary tumor in metastatic breast cancer: closing the barn door after the horse has bolted? J Clin Oncol 2006; 24:2694–2696. 6. Andre F, Slimane K, Bachelot T, et al. Breast cancer with synchronous metastases: trends in survival during a 14-year period. J Clin Oncol 2004; 22:3302–3308. 7. Giordano SH, Buzdar AU, Smith TL, et al. Is breast cancer survival improving? Cancer 2004; 100:44–52. 8. Le Scodan R, Stevens D, Brain E, et al. Breast cancer with synchronous metastases: survival impact of exclusive locoregional radiotherapy. J Clin Oncol 2009; 27:1375–1381. 9. Ruiterkamp J, Ernst MF, van de Poll-Franse LV, et al. Surgical resection of the primary tumor is associated with improved survival in patients with distant metastatic breast cancer at diagnosis. Eur J Surg Oncol 2009; 35: 1146–1151. 10. Rao R, Feng L, Kuerer HM, et al. Timing of surgical intervention for the intact primary in stage IV breast cancer patients. Ann Surg Oncol 2008; 15:1696–1702. 11. Rapiti E, Verkooijen HM, Vlastos G, et al. Complete excision of primary breast tumor improves survival of patients with metastatic breast cancer at diagnosis. J Clin Oncol 2006; 24:2743–2749. 12. Khan SA, Stewart AK, Morrow M. Does aggressive local therapy improve survival in metastatic breast cancer? Surgery 2002; 132: 620–627. 13. Simpson JS, Ma G, Holloway CM. Imaging technologies in breast diagnosis and surgical treatment. Minerva Chir 2011; 66:455–468. 14. Zhao Z, Wu F. Minimally-invasive thermal ablation of early-stage breast cancer: a systemic review. Eur J Surg Oncol 2010; 36:1149–1155. 15. Wang H, Littrup PJ, Duan Y, et al. Thoracic masses treated with percutaneous cryotherapy: initial experience with more than 200 procedures. Radiology 2005; 235:289–298.
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16. Atwell TD, Farrell MA, Leibovich BC, et al. Percutaneous renal cryoablation: experience treating 115 tumors. J Urol 2008; 179:2136–2140. 17. McMenomy BP, Kurup AN, Johnson GB, et al. Percutaneous cryoablation of musculoskeletal oligometastatic disease for complete remission. J Vasc Interv Radiol 2013; 24:207–213. 18. Littrup PJ, Bang HJ, Currier BP. Soft-tissue cryoablation in diffuse locations: feasibility and intermediate term outcomes. J Vasc Interv Radiol 2013; 24:1817–1825. 19. Rewcastle JC, Sandison GA, Muldrew K, et al. A model for the time dependent three-dimensional thermal distribution within iceballs surrounding multiple cryoprobes. Med Phys 2001; 28:1125–1137. 20. Permpongkosol S, Nicol TL, Khurana H, et al. Thermal maps around two adjacent cryoprobes creating overlapping ablations in porcine liver, lung and kidney. J Vasc Interv Radiol 2007; 18:283–287. 21. Littrup PJ, Jallad B, Vorugu V, et al. Lethal isotherms of cryoablation in a phantom study: effects of heat load, probe size and number. J Vasc Interv Radiol 2009; 20:1343–1351. 22. Gage AA, Baust JM, Baust JG. Experimental cryosurgery investigations in vivo. Cryobiology 2009; 59:229–243. 23. Manenti G, Perretta T, Gaspari E, et al. Percutaneous local ablation of unifocal subclinical breast cancer: clinical experience and preliminary results of cryotherapy. Eur Radiol 2011; 21:2344–2353. 24. Pusceddu C, Capobianco G, Meloni F, et al. CT-guided cryoablation of both breast cancer and lymph node axillary metastasis. Eur J Gynaecol Oncol 2011; 32:224–225. 25. Littrup PJ, Jallad B, Chandiwala-Mody P, et al. Cryotherapy for breast cancer: a feasibility study without excision. J Vasc Interv Radiol 2009; 20:1329–1341. 26. Pfleiderer SO, Marx C, Camara O, et al. Ultrasound-guided, percutaneous cryotherapy of small (o or ¼ 15 mm) breast cancers. Invest Radiol 2005; 40:472–477. 27. Pfleiderer SO, Freesmeyer MG, Marx C, et al. Cryotherapy of breast cancer under ultrasound guidance: initial results and limitations. Eur Radiol 2002; 12:3009–3014. 28. Huang EH, Tucker SL, Strom EA, et al. Predictors of locoregional recurrence in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy, mastectomy and radiotherapy. Int J Oncol Biol Phys 2005; 62:351–357.
