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Clinical Observations |
1 Section of Interventional Radiology and Image Guided Therapies, Memorial
Sloan-Kettering Cancer Center, 1275 York Ave., Rm. H118, New York, NY
10021.
2 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer
Center, New York, NY.
3 Section of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York,
NY.
4 Section of Gastrointestinal Surgery, Memorial Sloan-Kettering Cancer Center,
New York, NY.
Received March 9, 2007;
revised May 18, 2007;
Address correspondence to C. T. Sofocleous
(sofoclec{at}mskcc.org).
Abstract
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CONCLUSION. Radiofrequency ablation of breast cancer hepatic metastases is safe and may be used to control hepatic deposits in patients with stable or no extrahepatic disease.
Keywords: breast cancer • breast cancer metastases • liver metastases • liver tumors • radiofrequency ablation
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Although chemotherapy has historically been the main treatment for patients with metastatic breast cancer, response rates have been low in patients with disseminated breast metastases that involved the liver [2]. In recent small series of selected patients with hepatic metastases, regional chemotherapy with metastasectomy [3] and metastasectomy with systemic chemotherapy had a survival advantage when compared with chemotherapy regimens alone [3–7]. In a subset of this population, radiofrequency ablation was performed before resection [4]. Radiofrequency ablation and its benefits in selected patients with liver metastases from malignancies such as colorectal cancer have been reported [8–12].
Prior clinical series of radiofrequency ablation in the management of breast hepatic metastasis reported the results in 24 and 14 patients, respectively, most of whom had metastatic disease confined to the liver [13, 14]. A recent series of radiofrequency ablation for the management of hepatic metastases from breast cancer included 11 of 19 patients with stable extrahepatic disease, showing success in hepatic disease control and survival, particularly in patients with disease confined to the liver [15]. Our series describes the results of radiofrequency ablation in the management of breast cancer metastases to the liver in a selected population with a significantly larger proportion (10/12) of extrahepatic metastatic load at the time of the radiofrequency ablation.
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Patients
During the defined 6-year interval, 12 women (age range, 27–69 years;
median, 55 years) underwent radiofrequency ablation for the management of
hepatic metastases from breast cancer and were the subjects of the study.
Clinical information, including breast surgery, histology, receptor status,
and adjuvant therapy, is listed in Table
1. Lesion characteristics are shown in
Table 2. The interval between
the diagnoses of initial breast cancer and evidence of liver metastases was
13–168 months (median, 83 months). At the time of radiofrequency
ablation, two patients had metastatic disease limited to the liver and 10 had
stable extrahepatic disease, defined as extrahepatic metastatic deposits with
radiographic evidence of stability for at least 6 months
(Table 3). All patients signed
an informed consent.
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Indications and Contraindications for Radiofrequency Ablation
In our institution, indications for liver radiofrequency ablation are up to
three liver metastases with a combined diameter of less than 12 cm (largest
tumor with < 7 cm) in patients with new or growing liver metastases, with
no evidence of extrahepatic disease or in the face of stable extrahepatic
metastases.
Multiple (> 3) liver metastases, progressive extrahepatic metastases, coagulopathy (platelet count < 50 x 103/µL; international normalized ratio [INR], > 1.5), and liver failure were considered contraindications to the procedure.
Procedure Planning
Diagnostic workup included a contrast-enhanced abdominal CT examination.
Treatment decision was based on biopsy-proven breast metastases (8/12
patients) or imaging evidence of growing masses in patients with known
metastatic disease from breast cancer. Liver function, coagulation profile
(INR), and complete blood count tests were checked within a week before the
procedure. A platelet count of more than 50 x 103/µL and
an INR of less than 1.5 were required before the procedure. An anesthesiology
consultation for clearance was obtained before the procedure.
Technique
All procedures were performed under general anesthesia while the patients
were monitored by an anesthesiologist. The procedures were performed using CT
guidance and a standard sterile technique. Prophylactic antibiotics were
administered to all patients and consisted of cefazolin, 1 g IV, just before
the procedure and repeated every 8 hours over a 24-hour period.
Targeting and Treatment
A limited unenhanced CT examination (kVp, 120; mA, 400; slice thickness,
5–10 mm) was always performed to localize the lesion. Radiofrequency
ablation was performed using the Radio-Therapeutics (radiofrequency 3,000;
Boston Scientific) Leveen (n = 7 patients) and the RITA probe
(n = 5 patients) (Starburst XL, Generator 1500 X, RITA Medical
Systems).
Accurate needle and tine position to cover the entire lesion was confirmed with CT before the initiation of radiofrequency ablation. In all cases, grounding was achieved with the appropriate pads for each device. The pads were positioned on the upper thighs, ensuring good contact with the skin. During the procedure, the pads were frequently evaluated to ensure there was no overheating in order to prevent skin burns.
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After radiofrequency ablation, unenhanced CT was performed through the lesion to evaluate for bleeding at the treatment site. The patients recovered in the anesthesia recovery unit and were observed overnight in accordance with established institutional practice. Prolonged stay was recorded.
Treatment Assessment and Follow-Up
Immediately after the completion of the radiofrequency ablation procedure,
a limited unenhanced CT study was performed. The first imaging after treatment
consisted of contrast-enhanced CT within 6 weeks that was performed to
evaluate residual tumor at the treated site.
Routine follow-up thereafter was performed with contrast-enhanced CT every 3 months. Technique effectiveness was evaluated at the first contrast-enhanced CT examination 6 weeks after the procedure. Lack of enhancement of the ablated tumor with no evidence of irregular peripheral enhancement was considered complete ablation of the macroscopic tumor and a technically successful radiofrequency ablation session [16]. Irregular or nodular peripheral enhancement of the ablated area within 6 weeks of initial treatment was considered residual tumor at the ablation margin and a treatment failure [16].
Nodular or irregular enhancement seen during follow-up imaging (after 6 weeks) was considered suspicious for local tumor progression [16]. Repeat treatment was performed to treat local tumor progression and new intrahepatic focal lesions in patients who had fewer than three foci of intrahepatic tumor with a combined largest diameter less than 12 cm and radiologic evidence of stable extrahepatic disease.
Treatment assessment was performed using the Kaplan-Meier method to evaluate primary and intervention-assisted local progression-free intervals and overall survival since the initial diagnosis and after radiofrequency ablation.
Definitions
"Primary local progression-free interval" was defined as the
time interval between the initial radiofrequency ablation treatment and
follow-up imaging showing local tumor progression
(Fig. 1).
"Intervention-assisted local progression-free interval" was defined as the cumulative time between the initial radiofrequency ablation treatment and the latest follow-up imaging showing local tumor progression. This time interval includes the time between radiofrequency ablation sessions for the treatment of the same tumor (Fig. 2).
"Survival after radiofrequency ablation" was defined as the time interval between the first radiofrequency ablation session and the patient's death (Fig. 3).
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"Side effects" were defined as expected undesired consequences of the procedure that may often occur after radiofrequency ablation but rarely result in substantial morbidity.
"Length of stay" was defined as the time interval from the day of a radiofrequency ablation session until the patient's discharge from the hospital.
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Thirteen of 14 lesions in 12 patients were successfully treated on the basis of CT examinations performed within 6 weeks (mean interval, 37 days) after radiofrequency ablation to evaluate the presence of residual tumors.
The single lesion that was not completely treated was also the largest in the series, having a diameter of 6.4 cm. The mass was treated with five overlapping ablation treatments in the first sitting in an effort to achieve good coverage of the lesion. During evaluation by contrast-enhanced CT 34 days after radiofrequency ablation, evidence of residual tumor at the ablation site and of multifocal intrahepatic tumor progression was seen.
Primary Local Progression-Free Interval
We had one initial treatment failure. Six treated lesions remained necrotic
as of our latest follow-up (Fig.
5A,
5B,
5C,
5D). Although our routine
clinical protocol requires follow-up at 3-month intervals, two patients missed
their 3-month scheduled contrast-enhanced CT examinations, were imaged at 4
months, and were found to have local tumor progression.
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Intervention-Assisted Local Progression-Free Interval
Repeat radiofrequency ablation was performed to treat local disease
progression [2] and new lesions
[1]. One patient underwent
three radiofrequency ablation sessions to treat a new lesion and subsequently
local progression of two previously treated lesions, achieving
intervention-assisted local control of 47 months. A second and a third patient
underwent radiofrequency ablation to treat local progression, resulting in
overall interventionassisted local control of 16 and 11 months, respectively.
New intrahepatic distal lesions occurred in three patients, whereas two of the
primary treated lesions remained necrotic at 47 and 60 months (Fig.
6A,
6B,
6C) and one progressed at 12
months. We did not perform repeat radiofrequency ablation to treat this last
patient because of the size of the new intrahepatic distal lesion that she
developed (Fig. 6A,
6B,
6C). A median
intervention-assisted local progression-free interval of 47 months was
achieved with a mean of 1.3 radiofrequency ablation sessions per patient
(Fig. 2).
Another patient had two simultaneous radiofrequency ablation sessions to treat two liver metastases. Two patients with local tumor progression and with no extrahepatic disease were treated with hepatectomy. For the calculation of the intervention-assisted local progression, their time to local progression was considered an end point. As of the last follow-up, both of these patients are alive and without liver disease at 72 and 12 months after initial radiofrequency ablation.
Survival After Radiofrequency Ablation
Median and mean follow-ups were 22.5 and 29.4 months (range, 3–72
months) (n = 12). During follow-up, four patients died, two as a
result of disease progression without local tumor progression. The other two
had evidence of local progression at 7 and 16 months, respectively.
The median overall survival after radiofrequency ablation was 60 months (Fig. 3). The 3- and 5-year overall survival rates after radiofrequency ablation were 70% and 30%, respectively (Fig. 3).
Survival After Initial Diagnosis
Median survival was also calculated after the initial diagnosis of breast
cancer and was 145 months (Fig.
4).
Complications
Postprocedure complications included prolonged (36 hours) shoulder pain
that required treatment. This patient underwent radiofrequency ablation of a
lateral sector lesion with excellent results (Fig.
5A,
5B,
5C,
5D). The pain was located at
the left shoulder and was attributed to the position of the arm above the head
during radiofrequency ablation in a patient who probably had rotator cuff
injury (MRI showed joint effusion). The pain required medication for analgesia
(hydromorphone every 4–6 hours for 36 hours) after the procedure. The
pain resolved on the third day, and the patient was discharged on the fourth
day after radiofrequency ablation without further complaint.
Side Effects
Side effects included one asymptomatic right pleural effusion that was
documented on follow-up imaging and required no treatment.
Length of Stay
The median length of stay for all patients (n = 12) was 2 days
(range, 1–5 days).
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Usually, therapy for metastatic breast cancer consists of chemotherapy or endocrine therapy because even in the case of isolated metastases in one organ, diffuse tumor cell dissemination exists. Recent advances in local therapy such as surgical resection and radiofrequency ablation combined with effective systemic treatment have been applied in the management of patients with advanced breast cancer [13–15, 18, 19].
Surgical resection is considered the standard treatment in patients with colorectal cancer liver metastases with well-defined lesions for which clear margins are technically feasible and when there is no evidence of extrahepatic disease [8]. Metastasectomy in cases of breast cancer remains controversial but has shown promising results in selected patients, with previous small series reporting a 5-year overall survival rate of 41% [6]. The patients undergoing resection also received adjuvant local or systemic chemotherapy [6]. That same series concluded that hepatectomy is beneficial in selected patients with solitary liver metastases and a low surgical risk [6]. However, solitary liver metastases in breast cancer patients are rare, occurring in only 4–5% of all cases [18].
Radiofrequency ablation is widely accepted in the local treatment of hepatocellular carcinoma and limited colorectal liver metastases, with results that encourage its use in patients with other metastases, including those from breast cancer [19, 20]. Radiofrequency ablation is a good alternative treatment in the management of high-risk surgical patients and in those with stable extrahepatic disease who are not candidates for resection [19].
Our series describes the results in a group of 12 breast cancer patients with hepatic metastases, most of whom (n = 10 patients) presented with extrahepatic disease at the time of the radiofrequency ablation. The best results in terms of local tumor control were noted in patients with lesions smaller than 4 cm in diameter. The longest local progression-free interval was documented in a right hepatic lobe tumor measuring 1.8 cm. The patient was monitored closely with imaging and had disease progression in the left lobe and extrahepatic disease that led to her death. The initially treated tumor was necrotic in her last follow-up at 60 months after the initial radiofrequency ablation. Unfortunately, between the initial radiofrequency ablation session and the development of the second lesion in the left liver, the patient was outside the country and when she returned the new lesion was too big (7 cm) for ablation.
In our series, repeat radiofrequency ablation was performed in three patients to treat lesions that locally progressed and new tumors that developed distal to the initially treated tumor. Using this approach, prolonged local control was achieved, providing a median intervention-assisted local progression-free interval of 47 months. We believe that with diligent imaging and aggressive treatment of local progression and new intrahepatic tumors, better results can be achieved. Successful ablation was achieved in 13 (93%) of 14 treated lesions, documented as complete necrosis at the 6-week posttreatment contrast-enhanced CT examination.
The purpose of this examination (6-week posttreatment CT) was not the evaluation of local tumor progression (recurrence) but the confirmation that no residual tumor remained in the area treated by radiofrequency ablation. We believe in the necessity of a method to evaluate the success of radiofrequency ablation, and contrast-enhanced CT within 6 weeks is a reasonable method to do that [21]. When lesions that progressed in 4 months from treatment are included, the technique effectiveness [21] is 11 (79%) of 14. In a prior study that treated 64 liver metastases from breast cancer in 24 patients, a 92% complete necrosis was noted [13]. Most of the patients (16/24) in that study had disease limited to the liver, and 40 of 64 treated tumors were smaller than 2 cm [13]. Technique effectiveness based on the 6-month contrast-enhanced CT follow-up was 88% in a recent small series of 14 patients having treated lesions with a mean largest diameter of 1.90 cm [14].
In our population, in six (50%) of 12 patients the treated lesions remained necrotic as of our last follow-up (range, 3–72 months; median, 22.5 months), with a median overall survival after the radiofrequency ablation procedure of 60 months. The 3- and 5-year overall survival rates after radiofrequency ablation were 70% and 30%, respectively (Fig. 3). The largest previous radiofrequency ablation series reported 63% of the patients were disease-free and were followed up for 4–44 months [13]. Unfortunately, progression-free interval and overall survival curves were not calculated in that study and more direct comparisons and discussion are not possible. A 1-year survival rate of 64% was reported in a series that treated 14 patients [14], and a 30-month survival rate of 41.6% was recorded in a similar study that treated 19 patients, including 11 with stable extrahepatic disease [15].
Although our results appear to be similar to those reported in a resection series by Pocard et al. [7] in which the 3-year survival rate was 71% and to those in a study by Elias et al. [6] in which the survival rate was 50%, any direct comparison is impossible because the populations and reporting methods are different.
In a surgical series [4], hepatectomy (with or without radiofrequency ablation) was used to treat breast cancer liver metastases having a median diameter of 2.5 cm. That resulted in a 13-month median time to recurrence and median overall survival of 25 months after resection. Our median primary progression-free interval of 12 months is identical to that in this series, and our median survival of 60 months after ablation compares favorably. The contribution of radiofrequency ablation on liver metastatic load debulking may have some effect on survival, but in our (and most) series, patients received chemotherapy before and after the radiofrequency ablation. However, by no means should the overall survival results of this small series be attributed to the ablation treatment alone. In the same way, we stress that radiofrequency ablation was applied in a small and selected percentage of patients who had new or growing tumors in the liver in the face of controllable extrahepatic disease and no other focus of metastasis. Therefore, the findings of this study do not apply to all breast cancer patients with liver metastases.
Finally, as in the treatment of colorectal metastases, the success of application of radiofrequency ablation in surgical candidates may be determined by the "test-of-time approach" [20]. According to this concept, radiofrequency ablation is applied as a treatment option to liver metastases while delaying resection to allow additional metastases that may be present but undetected to develop. With this approach, the number of relatively morbid resections is decreased in patients who will ultimately develop multifocal disease [20]. Using this concept, limited hepatectomy was applied in two of our patients who developed local tumor progression at 6 and 8 months after radiofrequency ablation with no evidence of distant disease. As of their last follow-up, both of these patients are alive and without liver disease at 72 and 12 months after the initial radiofrequency ablation.
A prospective randomized trial comparing systemic treatment alone and systemic treatment with radiofrequency ablation for selected breast cancer liver metastases is absolutely needed to show any advantage of the radiofrequency ablation group in local and overall disease control when compared with systemic treatment alone. We believe that the results of this small study are encouraging and in agreement with previously reported data [13] about radiofrequency ablation, at least as a method that can contribute to the local control of liver metastases from breast cancer.
In short, radiofrequency ablation is a safe procedure and may prove to be a beneficial treatment option when added to systemic treatment for the management of selected patients with liver metastases from breast cancer.
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