Current Status of Interventional Oncology for Breast Cancer Liver Metastases: Articles From the Official Show Daily for Synergy 2015

Breast cancer is the most common cancer in women and the second most frequent cause of cancer deaths in women after lung cancer in developed nations.¹ Half of patients with metastatic breast cancer (MBC) will be diagnosed with liver metastases over their course of treatment, and postmortem studies have demonstrated the liver to be a common site of metastatic disease (62% to 72%).^2,3 The purpose of this review is to highlight specific roles for interventional oncology and liver-directed therapy in treating patients with breast cancer liver metastases based on three assertions:

1. Breast cancer liver metastases represent a unique clinical challenge that can result in abdominal pain, impaired liver function, and limited systemic chemotherapy options.
2. Metastatic breast cancer is a heterogeneous disease and there are subgroups of patients who may derive significant benefit from locoregional therapy.
3. Interventional oncology treatments validated for other hepatic malignancies have low rates of failure and can potentially be applied in conjunction with systemic chemotherapy.

Sequential monotherapy, whereby patients are “treated to progression,” has widespread adoption with increased antitumor activity and reduced toxicity of single-line anthracycline and taxane agents, but hepatic disease can be difficult to treat.⁴ When isolated hepatic tumors are treated with systemic therapy, the liver is the initial site of post-treatment progression in 60% to 97% of patients⁵ and hepatic progression and/or compromised function can limit eligibility for future systemic chemotherapy.^6-8 Liver metastases are unlike extrahepatic disease; biochemical markers of hepatic dysfunction portend a worsened prognosis.⁹ Even if a patient tolerates therapy, chemotherapy regimens can stop working for several reasons and the cause of treatment failure is often unknown at the time of progression.^10-14 Patient-specific approaches are needed to identify mechanisms of failure and target time-dependent histologic and biologic aspects unique to the dynamic disease state, but further validation is required prior to routine clinical use.¹⁵ Without more targeted approaches, patients eventually exhaust the most effective options and go on to receive empirical treatments with nth-line chemotherapies with increasingly less antitumor activity and more toxicity until a “less is more” approach is favored.

Interventional Oncology and Breast Cancer

The mindset of interventional oncology clinicians is one with a goal to achieve “more with less;” to be less invasive and to offer more powerful therapies with less pain, less toxicity, and faster recovery. In the case of MBC, interventional oncologists can offer minimally invasive therapies to treat hepatic disease during a switch or break in active chemotherapy. In patients with stable extrahepatic disease and progressing liver tumors, liver-directed therapy can potentially help arrest hepatic progression and preserve liver function. If progression continues extrahepatically but the primary goal of care is symptom-related intervention for palliation of abdominal pain from a large hepatic mass (capsular stretch), then intra-arterial therapy may offer a higher chance of specifically stabilizing the hepatic disease burden. 

The value of locoregional therapy in MBC is debated, but recent data suggest there are some patients with oligometastatic disease who could benefit from locoregional therapy.16 In select patients who are surgical candidates, hepatic resection offers the best rate of complete tumor extirpation with 25% to 61% survival at 5 years.^17-23 However, fewer than 1% of patients ultimately undergo resection, as most have tumor distributions in the liver that limit the success of surgery or clinical issues that make them poor surgical candidates.¹⁶ Moreover, the liver is the most common site of recurrence following hepatic resections and recurrence after resection is common, occurring after a median time of 13 months.^19,20 In unresectable cases, liver-directed therapies with image-guided interventional oncology techniques such as ablation and intra-arterial therapy may benefit these complex patients. 

Percutaneous Metastatic Breast Cancer Tumor Ablation

Percutaneous image-guided tumor ablation (heating with radiofrequency or microwave energy or freezing with cryoablation) is a valuable treatment option in select patients with limited disease burden. Successful ablation requires lesion coverage (limited by size and large vessels resulting in heat-sink effects), a feasible number of lesions (usually ≤3), and safe location of needle placement to avoid damage to vital structures (diaphragm, bile ducts). Reports on radiofrequency ablation (RFA) have 29.9-month to 60-month median survivals with 20% to 32% 5-year survival.^24-28 Rates of technical effectiveness are high, consistently exceeding 88% to 90% in treated lesions.^24-29 Vogl et al implemented MRI-guided laser-induced interstitial thermotherapy (LITT), resulting in a median survival of 37.6 months (n=276).³⁰ 

Niu et al applied cryoablation with and without dendritic cell vaccination in several organ sites with liver-directed therapy in 41 cases.³¹ Severe complications occurred at rates notably higher than those observed for RFA or LITT and included liver hemorrhage (15%), capsular rupture requiring transfusion (5%), thrombocytopenia requiring transfusion (17%), and liver abscess (7%). Nonthermal approaches like electroporation and high-dose-rate brachytherapy may also be useful for lesions abutting vascular structures. Collettini et al applied high-dose-rate brachytherapy with iridium-192, reporting technical effectiveness as 100% with median OS of 18 months (n=37) and median progression-free survival of 8 months.³² There is significant need for comparative effectiveness trials for ablation versus chemotherapy and it is important to note differences in selection criteria limit retrospective comparisons of survival for different locoregional interventions.³³

Transarterial Therapies

For many patients, the number, size, shape, or location of their lesions does not allow for technically successful ablation. In these cases, hepatic disease can still be treated with transarterial therapies that introduce chemotherapy, radiotherapeutics, and/or embolic materials into the tumor vasculature. The most studied intra-arterial approach for unresectable liver metastases is radioembolization with glass or resin yttrium-90 microspheres.^34-45 This approach has several appealing attributes: (1) radioembolization is performed as an outpatient procedure; (2) breast cancers tend to be highly radiosensitive; (3) the mechanism of action is not limited by receptor status or chemotherapy resistance mechanisms; and (4) a pilot study suggests safety of combination with capecitabine46 and many patients go on to continue receiving systemic chemotherapy.⁴⁵ A brief summary of the larger published reports on radioembolization for MBC patients in the peer-reviewed literature are shown in Table 1. Radioembolization consistently arrests tumor growth with low rates of progressive disease in treated lesions for both resin^41-44,47 and glass devices⁴⁵ with few serious grade 3+ clinical toxicities. Median overall survival outcomes from these studies are 10 months to 14 months in patients with ≤25% tumor replacement in the liver. With the available safety data in heavily pretreated patients, earlier interventions that parallel recent phase 3 prospective randomized investigations for unresectable liver-dominant metastatic colorectal cancer (SIRFLOX, EPOCH, and FOXFIRE), may allow comparisons to systemic chemotherapy, and opportunities for chemoradiation in select patients.⁴⁶ 

Chemoembolization

Chemoembolization allows infusion of chemotherapy and embolotherapy directly into the tumor vasculature to increase local dosing while avoiding the toxicity profile of systemic administrations. Chemoembolization has been used to treat breast cancer liver metastases at some centers, but generalizability is limited by the variability of applied chemoembolization protocols including the drug(s) used, preparation, embolic material, and treatment location.^48-54 Protocols and outcomes for MBC patients from several reports are shown in Table 2. Cho et al tailored multiple cytotoxic agents and dose selection based on patients’ (n=10) history of systemic treatment and noted improved median survival in patients treated with doxorubicin vs those treated with gemcitabine or oxaliplatin.⁵⁰ Vogl et al completed a large series in 161 patients being downstaged to laser-induced thermotherapy with no early deaths or major complications reported.⁵³ Survival at 1 year and 3 years for successfully downstaged patients was similar to those following ablation. More data are needed for chemoembolization in these patients, especially for new drug-delivery technologies,⁵⁵ and the choice of drug cocktail may someday be guided by personalized medicine. 

Conclusion

Locoregional therapy to supplement iterations of systemic treatments has an increasing role for MBC patients. Interventional oncology can offer a variety of tools for tailored approaches depending on the goals of care. Future trials examining the role for liver-directed therapy in specific patient populations (i.e., those with chemoresistance) are needed to improve patient selection and maximize benefit.  

Editor’s note: This article first appeared in the Synergy Daily conference newspaper, available to attendees of the Synergy Miami interventional oncology meeting, published November 7, 2015. This article did not undergo peer review. Drs. Salem and Lewandowski report consultancy to BTG. Mr. Gordon reports no related disclosures.

Suggested citation: Gordon AC, Salem R, Lewandowski RJ. Current status of interventional oncology for breast cancer liver metastases: articles from the official show daily for Synergy 2015. Intervent Oncol 360. 2016;4(3):E32-E40.

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