Stereotactic radiotherapy in metastatic breast cancer

The Breast 41 (2018) 57e66

Contents lists available at ScienceDirect

The Breast journal homepage: www.elsevier.com/brst

Review

Stereotactic radiotherapy in metastatic breast cancer Marco Possanzini a, b, c, *, Carlo Greco a ~o Champalimaud, Lisbon, Portugal Radiotherapy Department, Fundaça ~o Champalimaud, Lisbon, Portugal Breast Unit Fundaça c Radiotherapy Department, Businco Oncological Hospital, Cagliari, Italy a

b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 29 December 2017 Received in revised form 9 May 2018 Accepted 21 June 2018 Available online 28 June 2018

The treatment of metastatic breast cancer is largely focused on systemic therapy. However, over the past decades, there has been growing interest in the use of metastasis-directed therapy in selected cases presenting with an oligometastatic phenotype, i.e. low disease burden with a more indolent biology. Identification of the oligometastatic breast cancer population has, so far, proven elusive. Stereotactic radiotherapy offers an effective, non-invasive approach to ablate metastatic disease both in the brain and in extra-cranial settings. The advent of advanced imaging techniques for target definition, along with the ability to achieve highly conformal dose deposition with steep dose fall-off, enable safe implementation of extreme hypofractionated and single fraction regimens with ablative intent. There is growing evidence that radiation-based treatments are more cost-effective when compared to other ablative modalities. This article provides preliminary evidence that metastasis-direct ablation, with advanced radiotherapy techniques, may play an important role in the management of metastatic breast cancer patients, potentially improving clinical outcomes with minimal toxicity. However, prospective randomized controlled trials are needed to further the understanding of the interaction between systemic therapy and ablative irradiation. Additionally, research in genomic and molecular profiling is needed to characterize metastatic breast cancer patients who will most likely benefit from such combined treatment approaches. © 2018 Elsevier Ltd. All rights reserved.

Keywords: Breast cancer Oligometastasis Metastasis Ablative radiotherapy Stereotactic radiotherapy

Contents 1.

2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 1.1. Oligometastatic breast cancer (OMBC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 1.2. Stereotactic radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 1.2.1. Technical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 1.2.2. Biological aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Stereotactic radiotherapy in OMBC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 2.1. Brain metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 2.2. Extracranial metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 2.3. Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 2.4. New integrated strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 2.5. Cost-effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Funding and acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

~o Champalimaud, Lisbon, Portugal. * Corresponding author. Radiotherapy Department, Fundaça E-mail addresses: [email protected], [email protected] (M. Possanzini). https://doi.org/10.1016/j.breast.2018.06.011 0960-9776/© 2018 Elsevier Ltd. All rights reserved.

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1. Introduction 1.1. Oligometastatic breast cancer (OMBC) Since Paget's first attempt [1] to decipher the natural history of metastatic breast cancer in modern times, several theories have been put forth. Hellman's “spectrum theory” of cancer metastases [2], envisaged the metastatic process as a continuum, ranging from locally indolent to widespread dissemination as a function of the clonal evolution of the tumor. Indeed, discrete molecular steps in metastatic progression have been clearly demonstrated [3e5]. The “hallmarks of cancer” defined by Hanahan and Weinberg [6,7] consist of distinctive and complementary capabilities that produce different transformations in cellular physiology that allow cells to survive, proliferate and disseminate. Genetic diversity generated by genome instability and tumor immunomodulation are involved in the process, along with the activation/suppression of specific oncogenes [8]. The sequence and degree in which these transformations occur is at the basis of the oligometastatic (OM) state proposed by Hellman and Weichselbaum [9], a condition where the disease displays limited metastatic capacity, with a maximum number of five metastases and a controlled primary disease. Multiple phase II and III prospective clinical trials using systemic therapy in metastatic breast cancer (MBC) [10e15] along with large retrospective series [16,17] [18], empirically reinforce the hypothesis of a peculiar biology behind the OM state by the sheer observation that about half of MBC patients presents with
2 detectable metastases. More recently, different patterns of microRNA expression have been shown to discriminate between the OM and the polimetastatic (PM) phenotype in irradiated patients [19,20], with significant differences in progression and survival rates [20e22]. Thus, primary tumor microRNA expression profiling in combination clinical features hold promise in the identification of OM patients who may benefit from local ablative therapies. 1.2. Stereotactic radiotherapy 1.2.1. Technical aspects Stereotactic radiosurgery (SRS) was introduced by Leksell in 1951 [23] with the aim to localize intracranial targets. Since then, the advent of advanced imaging techniques, along with the ability to achieve highly conformal dose deposition with steep dose falloff, have paved the way to extreme hypofractionated schemes (low number of sessions with higher dose per fraction) in the extracranial setting. Over the last decade, “on board” imaging systems for precise target alignmet before delivery [24] and other technological advances have been introduced to ensure optimal target coverage with reduced normal-tissue exposure [25]. For instance, fiducial markers may be used in certain anatomical settings as an aid for target detection during the planning phase and verification during each treatment session [26] and on-line tracking tools [27] are currently widely used to enable target motion assessment, thus fulfilling the plan dosimetric objectives. Faster treatment delivery using flattening filter-free (FFF) technology [28] may also help reduce delivery uncertainties. Whereas dedicated stereotactic radiotherapy platforms are commercially available, modern linear accelerators equipped with on-board imaging and other necessary tools can be effectively utilized to deliver intracranial stereotactic radiosurgery (SRS), as well as extra-cranial stereotactic radiotherapy with ablative intent (often referred to as SBRT or SABR) in a single event (Single Dose Radiotherapy, SDRT) or with a multisession hypofractionated regimens. 1.2.2. Biological aspects Compared to conventionally

fractionated

radiotherapy

(1.8e2.2 Gy per fraction), SRS and extreme hypofractionated regimens with dose per fraction >10Gy, exploit a different mode of cell kill [29]. Along with mitotic death induced by DNA double-strand breaks, additional mechanisms involving microvascular dysfunction [30,31], are responsible for the increase in single dose and extreme hypofractionation treatment efficacy. Post-treatment inflammatory effects, may also recruit immune cells into the tumor, such as tumor-associated macrophages (TAMs), polymorphonuclear neutrophils (PMNs), dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) [32]. DC recruitment, maturation, MHC class I and II on cell surface expression and presentation of antigens to cytotoxic T lymphocytes (CTLs) have been shown to increase following high-dose irradiation. T cell responses may induce an overexpression of immunomodulating molecules such as B7 family inhibitory ligands (e.g. programmed cell deathligands PD-L1 and PD-L2), or check-point molecules like lymphocyte activation gene-3 (LAG-3), Tim-3, cytotoxic T-lymphocyte antigen 4 (CTLA-4) [32]. Additionally, Interferons (IFNs), ILs, colony stimulating factors (CSF), tumor necrosis factor alpha (TNF-a) and tumor growth factor beta (TGF-b) may be differentially expressed at the site of radioablation. The complexity of the aforementioned biological interactions is postulated to be the underlying basis of the so-called abscopal effect, an out-field response to radiotherapy which has been observed after high-dose irradiation [33,34]. 2. Stereotactic radiotherapy in OMBC In recent years there has been a rapid increase in the use of ablative radiotherapy for OM disease. Available clinical evidence supporting local ablative treatments, however, mainly consist of single-arm observational studies with significant heterogeneity in terms of study design, OM definition, diagnostic modalities, disease free interval, thus hampering the extrapolation of solid conclusions. Nevertheless, metastasis-directed therapies have become common practice in the last fifteen years [35,36], predicated upon the potential to modify the natural history of the disease, i.e. to maintain no evidence of clinical disease (NED), to sustain relapse-free interval (RFI) and no recurrence of cancer after NED induction during the entire lifespan of the patient [37]. Median survivals from 50 months to more than 20 years have been reported by several studies in OMBC [38e44], supporting the hypothesis of an underlying different biology when compared with the 25.9% MBC patients 5-year overall survival (OS) reported by the SEER database Cancer Statistic Review [45]. It has been suggested that selection bias due to the more indolent biology of OM disease could favorably affect the survival rates described by observational studies [46e49], however, to date, no prospective randomized controlled trials have confirmed increased survival with the use of local ablative treatments. At any rate, there is a general consensus that ablative treatments in OMBC have clinically significant relevance. For instance, in oligometastasis disease with controlled primary tumor [50], the use of ablative RT may delay systemic therapy with its associated toxicities and quality-of-life deterioration [51]. 2.1. Brain metastasis The first Gamma Knife case report on brain metastasis was published in 1989 [52]. Since then, there has been a constant growth in the use of radiosurgery techniques both on dedicated technology as well as on linac-based platforms, with excellent clinical outcomes and competitive cost-effectiveness [53]. The outcomes of breast specific-SRS studies are summarized in Table 1. Phillips et al. [54] provide a comprehensive analysis on breast cancer brain metastasis (BCBM) management. The incidence BCBM has been estimated to be in the range of 10e15% of all brain

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59

Table 1 Brain metastasis stereotactic radiotherapy in breast cancer patients. Study

Patients/lesions (n)

Therapy (dose)

LC (%)

median OS (months)

Toxicity (grade)

Combs et al. [120], 2004

62/103

NA

15

1.5%
2

Muacevic et al. [121], 2004

151/620

94

10

10.6% G3

Golden et al. [122], 2008

87/NA

SRS (10e20 Gy) ± WBRT SRS (19 ± 4 Gy) ± GTR ± WBRT SRS (NA)

NA

Kased et al. [117], 2009

95/348 SRS

15.6 (<3 metastases) 16.9 (>3 metastases) 16 (exclusive SRS)

SRS (12e20 Gy) ± WBRT

81/455 recurrent after WBRT

Matsunaga et al. [123], 2010

101/600

Kondziolka et al. [124], 2011

350/1535

Caballero et al. [125], 2012

90/NA recurrent after WBRT 103/283

Xu et al. [66], 2012

OS (%)

90 (1-year) exclusive SRS 83 (2-year) exclusive SRS 73 (1-year) salvage SRS 69 (1-year) salvage SRS NA

SRS (8e30 Gy, median 19) SRS (NA)

NA

SRS (15e20 Gy)

NA

SRS (20 Gy) ± GTR ± WBRT

NA

11.7 (salvage SRS)

13 49 (1-year) 26 (2-year)

40 vs 63 (TN vs other, 1-year) 12 vs 29 (TN vs other, 3-year) 0 vs. 20 (TN vs other, 5-year)

Dyer et al. [126], 2012 Yamamoto et al. [127], 2012

51/NA 269/NA

SRS (NA) SRS (10e25 Gy, median 21)

NA NA

Vern-Gross et al. [63], 2012

154/NA

SRS (9e24 Gy, median 20) ± WBRT

NA

Yomo et al. [128], 2013

80/704

SRS (10e24 Gy, median 20) ± GTR ± WBRT

Yang et al. [60], 2014

136/186

SRS (NA)

84 (1-year) 70 (23-year) 86 vs 69 (1-year, þlapatinib vs. no lapatinib) 90 (1-year)

65 (1-year)

73 (2-year)

41 (2-year)

Cho et al. [62], 2015

131/NA

SRS (NA) ± GTR ± WBRT

10.6% radionecrosis

40 (1-year) 21 (2-year) 3.8 (5-year)

50 (1-year) 26 (2-year)

11.2

4% radionecrosis NA

9.3

NA

10 (TN)

NA

18 (others)

16.2 8.8

NA NA

9 (ER þ HER2-) 22 (ER þ HER2þ) 11 (ER-HER2þ) 7 (TN) 11.4

NA

17.6

16 (ER þ HER2-)

NA

1.2% G4 3.7% G3

9.2 (GPA group 1) 15.6 (GPA group 2) 25.1 (GPA group 3) 45.2 (GPA group 4)

NA

NA

26 (ER þ HER2þ) 23 (ER-HER2þ) 7 (TN) Geraud et al. [129], 2017

12

T-DM1 þ SRS (NA) ± WBRT in HER2þ

75 vs. 83.3 (þT-DM1 vs no T-DM1)

NA

50% vs 26% radionecrosis (þT-DM1 vs. no concurrent)

SRS ¼ Stereotactic Radiosurgery; GTR ¼ Gross Tumor Resection; WBRT ¼ Whole Brain Radiotherapy; Na ¼ Not Available; Triple Negative breast cancer subtype; GPA ¼ Graded Prognostic Assessment; T-DM1 ¼ Trastuzumab Emtansine.

metastases. Compared with historic series, there appears to be an increase in incidence, ranging between 3% and 6% in early-stage, and up to 30% in stage IV disease, likely due to more effective systemic treatments [54e58]. The Radiation Therapy Oncology Group (RTOG) Breast Cancer Graded Prognostic Analysis identified several independent factors for OS in BCBM, namely the Karnofsky performance status (KPS), age, number of lesions and tumor biology [59e61]. In particular, triple negative MBC patients have 25e46% estimated probability of brain recurrence, a shorter free interval from primary cancer diagnosis, with a median survival time of 3e12 months after metastasis diagnosis [62,63]. In HER2

positive disease brain progression usually occurs in controlled extra-cranial disease. Hormone receptor positive HER2 negative MBC have 10% probability of brain recurrence, usually with a delayed onset and, frequently, after several lines of hormonal therapy, with a median survival time after BM diagnosis of 15e17 months [54]. Historically, radioablative treatments have been performed alone or in combination with whole brain RT (WBRT), with or without the gross tumor removal [64]. Surgical resection and SRS have different clinical indications, largely based on lesion size, surgical accessibility, KPS and life expectancy. Surgery can relieve

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Fig. 1. (a). Baseline PET/CT. Solitary L5 metastasis from breast cancer with extensive involvement of the vertebral body (SUVmax 17.5). (b). Dose distribution of VMAT plan. Presciption dose 24 Gy to the PTV. 10 MV-Flattened Filter Free (FFF) beam. (c). 3 months post-single dose IGRT 24Gy Follow-up FDG-PET/CT conforms complete metabolic response (SUVmax <1) of the treated lesion and absence of elsewhere progression. (d). 36 Months post-treatment FDG-PET/CT conforms complete metabolic response (SUVmax <1) of the treated lesion and durable absence of elsewhere progression.

mass effect immediately, while SRS can treat inaccessible lesions to surgery in a noninvasively way and can simultaneously treat multiple lesions [65]. Non-operated BMBC patients have a 2-year local control rate of 83% [61] and 5-year OS rate of 20.4% [66]. WBRT alone appears to result in increased intra-cranial control and reduced neurologic deaths, albeit without a clear-cut benefit in OS [67]. In an effort to reduce potential treatment-related cognitive side effects post-WBRT, SRS has been attempted in patients with on 5e10 lesions or more [68,69] with encouraging outcomes. Volumetric modulated arc radiosurgery [70] can deliver doses to multiple sites, improving treatment compliance thanks to shorter treatment times. Post-neurosurgical removal, postoperative WBRT is usually recommended to improve intracranial control. However, there is increasing evidence that SRS may be used, instead, to defer WBRTinduced cognitive impairment. Fractionated stereotactic regimens are recommended for large surgical cavities (over 3 cm in maximum diameter) with similar control rate to SRS [71]. 2.2. Extracranial metastases Since 1995, when the first results of radioablative procedures outside of brain were published [72], SBRT has increasingly been applied in several anatomical sites. In a hypothesis-generating prospective study Milano et al. [43] reported on the outcomes of patients
5 detectable BC metastases treated with SBRT with curative intent. The 4-year LC, PFS and OS were 89%, 38% and 59%, respectively. On univariate analysis, statistically significant predictors of more favorable outcomes were the presence of a single lesion compared 5 lesions, bone only metastases or lesions not progressing on systemic therapy. With the hypofractionated regimen used in this study, gross tumor volume size was significantly associated with decreased local control. These results are consistent with three surgical series and one radiofrequency ablation study where lower lesion number and tumor burden resulted in longer OS [73e76]. In another study published by the Rochester

group [44], a greater net tumor volume predicted significantly worse outcomes and BCM patients fared significantly better compared to all other histologies, supporting aggressive local therapy use and different fractionation schemes with greater dose per fraction, specifically in breast cancer OM patients. In Kobayashi's series [38], single organ involvement was predictive for complete response. On univariate analysis, single organ involvement, use of local treatment, anthracycline-based chemotherapy and complete response were significantly associated with improved outcomes. Several series have explored the use of hypofractionated radiotherapy and single dose techniques in the management of non-complicated bony lesions [77,78]. In the most extensive study of pain relief in skeletal sites by single dose radiotherapy reported by Gerszten et al. [79]. the likelihood of tumor control was significantly better for breast histology. The results of a sub-group analysis of the 68 spinal metastases in 50 BC patients showed a 96% long-term symptomatic response and radiographic tumor control in all patients who underwent radiosurgery as their primary treatment modality [80]. In a series by Yamada et al. on the treatment of 362 patients with 412 spinal radiotherapy and surgery-naive, >90% 3-year local control in all histologies was reported, reaching levels of 98% in MBC [77]. FDG-PET CT scan may be effectively used to assess treatment outcomes, with preliminary data suggesting that the magnitude of change in metabolic uptake (DSUV) post-single fraction is predictive of long-term freedom from relapse [81,82]. Fig. 1 shows an ablative approach with single fraction image-guided radiotherapy in a patient with a solitary spine metastasis, indicating complete metabolic response at three month on the FDG-PET scan and freedom from local and systemic relapse at three years. Isolated metastases of the lung or pleural space are found in 15%e24% of patients with MBC. Modern adjuvant hormonal, chemotherapy and targeted therapy have not significantly improved median survival [83]. Due to the lack of specific SBRT trials on lung MBC, potential benefits must be extrapolated from

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61

Fig. 1. (continued).

non-specific lung SBRT series and lung metastasectomy. In a multiinstitutional phase I/II SBRT trial on lung metastases [84], the 1 and 2-year LC rates were 100% and 96%, respectively. Surgical series have reported 5, 10 and 15-year survival rates of 38e50%, 22e26% and 20e26% respectively [85]. Disease-free interval of 36 months, number of metastases and complete resection have been identified as favourable prognostic factors. Interestingly, Meimarakis et al. [86] showed significantly reduced OS in triple-negative patients. Several disease-specific factors, such as primary tumour stage [74,76,86,87], primary tumour grade and/or histology [74,76,86], prior recurrences [88,89], tumour marker levels [86] consistently affected OS. Adjuvant therapy regimen [76,86], and endocrine therapy for metastases [76] have also been reported to be associated with overall survival.

Approximately half of breast cancer patients develop liver progression, usually as a late occurrence in the natural history of the disease In approximately 35% of the cases it represents the first metastatic site [16] and the sole metastatic site in 18e25% of the cases [16,90]. Rarely are local ablative treatments for BC liver metastases considered a viable therapeutic option due to the concomitant involvement of additional target organs. Median survival in liver only MBC can exceed 2 years after systemic therapy in the triple negative subtype. Time to liver metastases <24 months and >3 lesions are regarded as significant predictors of poor survival [91]. Most patients fail to achieve long-term control of liver lesions following response to systemic therapy, suggesting a potential role for aggressive multimodality treatment [90]. To date, however, liver SBRT data is still limited. Promising results has been

62

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Fig. 1. (continued).

shown by a recent experience on 33 lesions in 22 liver MBC patients [92]. PFS was however relatively low. Following hepatic metastasectomy, median survival ranges between 15 and 63 months and 5-year survival rates between 12 and 61% [37], with solitary hepatic metastasis, normal hepatic reserve and long disease-free interval before hepatic progression representing predictors of improved clinical outcomes [93,94]. Breast-specific SBRT studies are very sparse in the literature (Table 2). Recently, a multicentre prospective phase II trial [95] enrolled 54 OMBC patients with 92 metastatic lesions. Forty-four were treated with SBRT, and 10 with fractionated IMRT. Sites of metastatic disease were mainly bone (60), lymph nodes (23), lung (4) and liver (5). At a median follow-up of 30 months (range, 6e55 months), the 1- and 2-year PFS were 75% and 53%, respectively and the 2 year LC and OS were 97% and 95%, respectively. An ongoing phase III trial is randomizing women with 1e2 breast cancer metastases to upfront ablation of all detectable lesions with either surgery or radiation along with standard of care systemic therapy versus standard of care systemic therapy alone (NCT02364557). This study will help to better define the role of

metastasis-directed treatment, be it surgery or radiation, in OM breast cancer. RNA/cDNA from liquid biopsies will be assessed as a potential tool for OM phenotype identification and patient selection for local ablative treatments. 2.3. Toxicity WBRT has been known to be associated with a decline of neurocognitive function and quality of life (QoL) [96]. The American Society for Radiation Oncology recommends avoiding adjuvant WBRT after SRS for patients with limited BM [97], although the topic is still open to scientific debate [98]. Acute toxicity is usually minimal after SRS/SFRT and it is a function of tumor size (treatment volume) and prescription dose [99]. Edema may develop in the treatment region but intracranial hypertension is uncommon. Radionecrosis is seen on magnetic resonance imaging in 20%e25% of the cases at approximately 9e12 months after treatment, however, this is symptomatic in <10% [52]. Risk factors for radionecrosis include prior SRS to the same lesion (with 20% 1-year risk of symptomatic radionecrosis), the volume of unaffected brain tissue

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Table 2 Stereotactic body radiotherapy in metastatic breast cancer patients. Study

Site

Patients/lesions (n)

Therapy (dose)

LC (%)

PFS (%)

OS (%)

Pain relief

Toxicity (grade)

Gertzen et al. [80], 2005

Spinal

NR

NR

96%

NA

Recurrent spinal after CRT Liver, lung, bone, Lymph nodes

sdSBRT (15e22.5 Gy, median 19 Gy) fSBRT (21e28 Gy/3-4fr.)

100

Gagnon et al. [118], 2007

50/68 (48 recurrent) 18/NA (17 recurrent) 40/85

NR

NR

median 21

Near complete


2

44 (2-year)

76 (2-year)

NA

89 (4-year) 98 (1-year)

38 (4-year) 48 (1-year)

59 (4-year) 93 (1-year)


2

90 (3-year)

27 (2-year)

66 (2-year)

96 (1-year)

35 (1-year)

92 (1-year)

G1 39%

87 (2-year) 97 (2-year)

18 (2-year) 75 (1-year)

66 (2-year) 95 (2-year)


2

Milano et al. [43], 2009

Scorsetti et al. [119], 2016

Lung, liver

22/33 liver, 10/14 lung

Scorsetti et al. [92], 2017

Liver

22/33

 et al. [95], 2018 Trovo

Bone, lymph nodes, lung, liver

54/92 (10 fractionated IMRT)

fSBRT (NA)

fSBRT (liver 56.25e75 Gy/3 fr., median 75 Gy) fSBRT (lung 48e60 Gy/3e4 fr., median 48 Gy/4fr.) fSBRT (56.25e75 Gy/3 fr., median 75 Gy) fSBRT (30e45 Gy/3fr.) or fIMRT (60 Gy/25 fr.)

53 (2-year) Note: VMAT ¼ Volumetric Modulated Arc Therapy; fSBRT ¼ fractionated Stereotactic Body Radiation Therapy; sdSBRT ¼ single dose Stereotactic Body Radiation Therapy; NA ¼ Not Available.

receiving > 10e12 Gy, and Capecitabine within 1 month of SRS [100]. A recent post-operative multicentric prospective randomized trial confirmed a decline in cognitive function with WBRT than with SRS without difference in overall survival suggesting that SRS radiosurgery should be considered one of the standards of care [101]. Extra-cranial SBRT and SDRT have been shown to be associated with excellent toxicity profiles. In lung SBRT the incidence of grade 3 toxicity was 8% [85]. In a recently reported a breast-specific SBRT series no Grade 3 toxicity was observed [96] (Table 2).

2.4. New integrated strategies Metastatic dissemination is responsible for the majority of cancer-related deaths. MBC is characterized by vast genomic and phenotypic diversity [102]. It has been speculated that clonal diversity generated by successive mutations is associated with the development of immunogenic neo-antigens, likely a necessary condition for the efficacy of checkpoint inhibition [103]. The combination of large doses of radiation on metastatic deposits along with the use of inhibitors of immunosuppressive pathways may stimulate anti-tumor immunity, potentially leading to a wider systemic effect of radiation beyond the treated site (i.e. the abscopal effect). The mechanisms by which this effect may be best elicited, the optimal radiation regimens and the potential effects on clinically relevant end-points represent, at present, a topic of scientific speculation. The underlying hypothesis is that the combination of large radiation doses and immunotherapy agents results in enhanced tumor antigen expression and facilitated priming of Tcells. In preclinical studies on breast cancer-bearing mice, the administration of an anti-CTLA-4 antibody and SBRT (2 fractions of 12 Gy), compared to the checkpoint inhibition alone, significantly improved survival by preventing the appearance of lung metastases [104e106]. It is noteworthy that CTLA-4 blockade alone did not achieve tumor response and exclusive SBRT resulted only in an increased local control. Long term tumor specific immunity, therefore, appears to be stimulated by the combined approach [107]. Common adverse reactions of immune checkpoint inhibitors are enterocolitis, hepatitis, adrenalitis, hypophysitis, uveitis, dermatitis, fatigue and musculoskeletal events [108,109].

An ongoing clinical trial involving combination therapy including 20 Gy ablative single dose irradiation (NCT02303366) aims to investigate the role of immunotherapy and radiation in OMBC. Other ongoing clinical trials on a variety of solid tumors will contribute to a better understanding of the combined effects and potential toxicity of immunotherapy with radiation and help define new treatment strategies [110]. 2.5. Cost-effectiveness Although local tumor control and favorable toxicity profiles are achievable with advanced technological platforms, this may come a higher cost compared to conventional radiotherapy. However, higher costs are largely mitigated by shorter treatment courses, patient convenience [111] and a reduction of several indirect costs [112,113]. As non-invasive treatment modality, radioablation is less expensive than alternative options requiring anesthesia and/or hospitalization [114,115] in most health systems. In two different critical reviews dealing with diverse clinical settings [114,116], radioablative modalities were dominant in incremental cost effectiveness ratio, (ICER) analysis, compared to surgery or conventional radiotherapy techniques. These studies, however, carry inherent limitations due to the lack of direct clinical and health economic comparison between treatment options, resource cost utilization unrelated to treatment, as well as lack of patient quality of life outcomes. 3. Conclusions This review provides preliminary evidence that ablative radiotherapy may play an important role in management of oligometastatic breast cancer and its use is rapidly gaining consensus due to its non-invasive nature, excellent safety profile, established efficacy in achieving durable local control in a cost-effective manner. However, most evidence is still limited to retrospective trails with relatively small patient number making it difficult to draw reliable conclusions. Ideally randomized controlled trials in patients with limited metastatic disease will clarify the role of ablative procedures alone or in combination with systemic treatments, including immunotherapy, potentially identifying individuals who most likely can benefit from such treatment approaches based on genomic profiling.

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Conflict of interest statement The Authors declare that they have no conflicts of interest to report. Funding and acknowledgements

[22]

[23] [24]

There are no funding sources to report relevant to this work. [25]

Ethical approval

[26]

No approval was required specifically for this paper. References [1] Paget S. Distribution of secondary growths in cancer of the breast. Lancet 1889;1:571e3. [2] Hellman S. Karnofsky memorial lecture. Natural history of small breast cancers. J Clin Oncol: Off J Am Soc Clin Oncol 1994;12:2229e34. https:// doi.org/10.1200/JCO.1994.12.10.2229. [3] Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002;2:563e72. https://doi.org/ 10.1038/nrc865. [4] Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 2003;3:453e8. https://doi.org/10.1038/ nrc1098. [5] Valastyan S. Tumor metastasis: molecular insights and evolving paradigms. Cell 2011;147:275e92. https://doi.org/10.1016/j.cell.2011.09.024. [6] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57e70. [7] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646e74. https://doi.org/10.1016/j.cell.2011.02.013. [8] Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006;127:679e95. https://doi.org/10.1016/j.cell.2006.11.001. [9] Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13(1): 8e10. https://doi.org/10.1200/JCO.1995.13.1.8. [10] Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 2003;21:588e92. https://doi.org/10. 1200/JCO.2003.08.013. [11] Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, et al. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 2008;26:3950e7. https://doi.org/10.1200/JCO.2007.11.9362. [12] Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, et al. AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol 2013;31:1719e25. https://doi.org/10.1200/JCO.2012.44.7912. [13] Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2- positive metastatic breast cancer. J Clin Oncol 2013;31:1157e63. https://doi.org/10.1200/ JCO.2012.44.9694. [14] Tawfik H, Rostom Y, Elghazaly H. All-oral combination of vinorelbine and capecitabine as first-line treatment in HER2/Neu-negative metastatic breast cancer. Cancer Chemother Pharmacol 2013;71:913e9. https://doi.org/10. 1007/s00280-013-2082-4. [15] Bergh J, Bondarenko IM, Lichinitser MR, Liljegren A, Greil R, Voytko NL, et al. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol 2012;30:921e9. https://doi.org/10.1200/JCO. 2011.35.7376. [16] Pentheroudakis G, Fountzilas G, Bafaloukos D, et al. Metastatic breast cancer with liver metastases: a registry analysis of clinicopathologic, management and outcome characteristics of 500 women. Breast Cancer Res Treat 2006;97(3):237e44. https://doi.org/10.1007/s10549-005-9117-4. [17] Dorn PL, Meriwether A, LeMieux M, et al. Patterns of distant failure and progression in breast cancer: implications for the treatment of OM disease. In: ASTRO annual meeting; 2011. October 2e6 Miami, FL. [18] Tait C, Waterwarth A, Loncaster J, et al. The oligometastatic state in breast cancer: hypothesis or reality. Breast 2005;14:87e93. https://doi.org/ 10.1016/j.breast.2004.10.003. [19] Lussier YA, Xing HR, Salama JK, et al. MicroRNA expression caracterizes oligometastasis(es). PLoS One 2011;6:e28650. https://doi.org/10.1371/ journal.pone.0028650. [20] Wong AC, Watson S, Pitroda S, et al. Clinical and molecular markers of longterm survival after oligometastasis-directed sterotactic body radiotherapy (SBRT). Cancer 2016;122(14):2242e50. https://doi.org/10.1002/cncr.30058. [21] Lussier YA, Khodarev NN, Regan K, et al. Oligo- and polymetastatic

[27]

[28]

[29]

[30] [31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45] [46]

[47]

progression in lung metastasis(es) patients is associated with specific microRNAs. PLoS One 2012;7:e50141. https://doi.org/10.1371/ journal.pone.0050141. Wong AC, Pitroda S, Watson S, et al. Long-term survivors of SBRT doseescalation study for oligometastases: clinical and molecular markers. Int J Radiat Oncol Biol Phys 2015;93(3):S64. €m L. Department of neurosurgery, Karolinska Institute: Lindquist C, Kihlstro 60 years. Neurosurgery 1996;39(5):1016e21. Boda-Heggemann J, Lohr F, Wenz F, et al. kV conebeam CT-based IGRT: a clinical review. Strahlenther Onkol 2011;187:284e91. https://doi.org/ 10.1007/s00066-011-2236-4. ICRU REPORT 91. Prescribing, recording, and reporting of stereotactic treatments with small photon beams. J ICRU 2014;14(2). €ussler SM, Muacevic A, et al. CT-fluoroscopy guided percutaTrumm CG, Ha neous fiducial marker placement for CyberKnife stereotactic radiosurgery: technical results and complications in 222 consecutive procedures. J Vasc Intervent Radiol 2014 May;25(5):760e8. https://doi.org/10.1016/ j.jvir.2014.01.004. Belanger M, Saleh Z, Volpe T, et al. Validation of the calypso surface beacon trasponder. J Appl Clin Med Phys 2016 Jul;17(4):223e34. https://doi.org/ 10.1120/jacmp.v17i4.6152. Xiao Y, Kry SF, Popple R, et al. Flattening filter-free accelerators: a report from the AAPM therapy emerging technology assessment work group. J Appl Clin Med Phys 2015 May 8;16(3):5219. https://doi.org/10.1120/ jacmp.v16i3.5219. Shuryak I, Carlson DJ, Brown JM, et al. High-dose and fractionation effects in stereotactic radiation therapy: analysis of tumor control data from 2965 patients. Radiother Oncol 2015;115:327e34. https://doi.org/10.1016/ j.radonc.2015.05.013. Fuks Z, Kolesnick R. Engaging the vascular component of the tumor response. Cancer Cell 2005;8:89e91. https://doi.org/10.1016/j.ccr.2005.07.014. Park HJ, Griffin RJ, Hui S, et al. Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). Radiat Res 2012;177:311e27. Popp I, Grosu AL, Niederman G, et al. Immune modulation by hypofractionated stereotactic radiation therapy: therapeutic implications. Radiother Oncol 2016;120:185e94. https://doi.org/10.1016/j.radonc.2016.07.013. Finkelstein SE, Timmerman R, McBride WH, et al. The confluence of stereotactic ablative radiotherapy and tumor immunology. Clin Dev Immunol 2011;2011, 439752. https://doi.org/10.1155/2011/439752. Seyedin SN, Schoenhals JE, Lee DA, et al. Strategies for combining immunotherapy with radiation for anticancer therapy. Immunotherapy 2015;7: 967e80. https://doi.org/10.2217/imt.15.65. Lewis SL, Porceddu S, Nakamura N, et al. Definitive stereotactic body radiotherapy (SBRT) for extracranial oligometastases: an international survey of >1000 radiation oncologists. Am J Clin Oncol 2015. https://doi.org/ 10.1097/COC.0000000000000169. Bartlett EK, Simmons KD, Wachtel H, et al. The rise in metastasectomy across cancer types over the past decade. Cancer 2015;121:747e57. https://doi.org/ 10.1002/cncr.29134. Cheng YC, Ueno NT. Improvement of survival and prospect of cure in patients with metastatic breast cancer. Breast Cancer 2012;19:191e9. https://doi.org/ 10.1007/s12282-011-0276-3. Kobayashi T, Ichiba T, Sakuyama T, et al. Possible clinical cure of metastatic breast cancer: lessons from our 30-year experience with OM breast cancer patients and literature review. Breast Cancer 2012;19(3):218e37. https:// doi.org/10.1007/s12282-012-0347-0. Kucharczyc MJ, Parpia S, Walker-Dilks C, et al. Ablative therapies in metastatic breast cancer: a syestematic review. Breast Cancer Res Treat 2017;164: 13e25. https://doi.org/10.1007/s10549-017-4228-2. Friedel G, Pastorino U, Ginsberg RJ, et al. Results of lung metastasectomy from breast cancer: prognostic criteria on the basis of 467 cases of the International Registry of Lung Metastases. Eur J Cardio Thorac Surg 2002;22(3): 335e44. Yhim HY, Han SV, Oh DY, et al. Prognostic fators for recurrent breast cancer patients with an isolated, limited number lung metastases and implication for pulmonary metastasectomy. Cancer 2010;116(12):2890e901. https:// doi.org/10.1002/cncr.25054. Geiger S, Cnossen JA, Horster S, et al. Long-term follow-up in patients with metastatic breast cancer: results of a retrospective, single-center analysis from 200 to 2005. Anti Cancer Drugs 2011;22(9):933e9. https://doi.org/ 10.1097/CAD.0b013e32834860af. Milano MT, Zhang H, Metcalfe SK, et al. OM breast cancer treated with curative-intent stereotactic body radiation therapy. Breast Cancer Res Treat 2009;115:601e8. https://doi.org/10.1007/s10549-008-0157-4. Milano MT, Katz AW, Zhang H, Okunieff P. Oligometastases treated with stereotactic body radiotherapy: long-term follow-up of prospective study. Int J Radiat Oncol Biol Phys 2012;83(3):878e86. https://doi.org/10.1016/ j.ijrobp.2011.08.036. Howlader NA, Krapcho M,, Garshell J, et al., editors. SEER cancer statistics review, 1975e2012. Bethesda, MD: National Cancer Institute; April 2015. Palma DA, Louie AB, Rodrigues GB. New strategies in stereotactic radiotherapy for oligometastases. Clin Cancer Res 2015;21:5198e204. https:// doi.org/10.1158/1078-0432.CCR-15-0822. Macbeth F, Treasure T. Stereotactic ablative radiotherapy for

M. Possanzini, C. Greco / The Breast 41 (2018) 57e66

[48] [49] [50]

[51]

[52] [53]

[54] [55] [56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

'oligometastases': a treatment in search of evidence. Clin Oncol (R Coll Radiol) 2016. https://doi.org/10.1016/j.clon.2015.12.025. Aberg T, Malmberg KA, Nilsson B, et al. The effect of metastasectomy: fact or fiction? Ann Thorac Surg 1980;30:378e84. Salama JK, Milano MT. Radical irradiation of extracranial oligometastases. J Clin Oncol 2014;32:2902e12. https://doi.org/10.1200/JCO.2014.55.9567. Niibe Y, Hayakawa k. Oligometastases and oligo-recurrence: the new era of cancer therapy. Jpn J Clin Oncol 2010;40:107e11. https://doi.org/10.1093/ jjco/hyp167. Palma DA, Salama JK, Lo SS, et al. The OM state Separating truth from wishful thinking. Nat Rev Clin Oncol 2014;11:549e57. https://doi.org/10.1038/ nrclinonc.2014.96. Lindquist C. Gammaknife surgery for recurrent solitary metastasis of a cerebral hypernephroma: case report. Neurosurgery 1989;25:802e4. Lee WY, Cho DY, Lee HC, Chuang HC, Chen CC, Liu JL, et al. Outcomes and cost-effectiveness of gamma knife radiosurgery and whole brain radiotherapy for multiple metastatic brain tumors. J ClinNeurosci 2009;16:630e4. https://doi.org/10.1016/j.jocn.2008.06.021. Phillips C, Jeffree R, Khasraw M. Management of BC BM: a practical review. Breast 2017;31:90e8. https://doi.org/10.1016/j.breast.2016.10.006. Pestalozzi BC. Brain metastases and subtypes of breast cancer. Ann Oncol 2009;20:803e5. https://doi.org/10.1093/annonc/mdp246. Dawood S, Broglio K, Esteva FJ, et al. Survival among women with triple receptor-negative breast cancer and brain metastases. Ann Oncol 2009;20: 621e7. https://doi.org/10.1093/annonc/mdn682. Tham YL, Sexton K, Kramer R, et al. Primary breast cancer phenotypes associated with propensity for central nervous system metastases. Cancer 2006;107:696e704. https://doi.org/10.1002/cncr.22041. Pestalozzi BC, Zahrieh D, Price KN, et al. Identifying breast cancer patients at risk for central nervous system (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann Oncol 2006;17:935e44. https:// doi.org/10.1093/annonc/mdl064. Sperduto P, Kased N, Roberge D, Xu Z, Shanley R, Luo X, et al. Effect of tumour subtype on survival and the graded prognostic assessment for patients with breast cancer and brain metastases. Int J Radiat Biol Oncol Phys 2012;82(5): 2111e7. https://doi.org/10.1016/j.ijrobp.2011.02.027. Yang TJ, Oh JH, Folkert MR, et al. Outcomes and prognostic factors in women with 1 to 3 breast cancer brain metastases treated with definitive stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 2014;90(3). 518e525, https:// doi.org/10.1016/j.ijrobp.2014.06.063. Subbiah IM, Lei X, Weinberg JS, Sulman EP, Chavez-MacGregor M, Tripathy D, et al. Validation and development of a modified breast graded prognostic assessment as a tool for survival in patients with breast cancer and brain metastases. J Clin Oncol 2015;33(20):2239e45. https://doi.org/ 10.1200/JCO.2014.58.8517. Cho E, Rubinstein L, Stevenson P, et al. The use of stereotactic radiosurgery for brain metastases from breast cancer: who benefits most? Breast Cancer Res Treat 2015;149:743e9. https://doi.org/10.1007/s10549-014-3242-x. Vern-Gross TZ, Lawrence JA, Case LD, McMullen KP, Bourland JD, MethenyBarlow LJ, et al. Breast cancer subtype affects patterns of failure of brain metastases after treatment with stereotactic radiosurgery. J Neuro Oncol 2012;110(3):391e8. https://doi.org/10.1007/s11060-012-0976-3. Amsbaugh MJ, Boling W, Woo S. Tumor bed radiosurgery: an emerging treatment for brain metastases. J Neuro Oncol 2015;123:197e203. https:// doi.org/10.1007/s11060-015-1789-y. Fontanella C, De Carlo E, Cinausero M, et al. Central nervous system involvement in breast cancer patients: is the therapeutic landscape changing too slowly. Cancer Treat Rev 2016;46:80e8. https://doi.org/10.1016/ j.ctrv.2016.03.014. Xu Z, Schlesinger D, Toulmin S, Tyvin R, Sheeran J. Impact of triple-negative phenotype on prognosis with breast cancer brain metastases. Int J Radiat Biol Phys 2012;84(3):612e8. https://doi.org/10.1016/j.ijrobp.2011.12.054. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 2011;29:134e41. https://doi.org/10.1200/JCO.2010.30.1655. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014;15:387e95. https:// doi.org/10.1016/S1470-2045(14)70061-0. Grandhi R, Kondziolka D, Panczykowski D, et al. Stereotactic radiosurgery using the Leksell Gamma Knife Perfexion unit in the management of patients with 10 or more brain metastases. J Neurosurg 2012;117:237e45. Nath SK, Lawson JD, Simpson DR, et al. Single-isocenter frameless intensitymodulated stereotactic radiosurgery for simultaneous treatment of multiple brain metastases: clinical experience. Int J Radiat Oncol Biol Phys 2010;78: 91e7. https://doi.org/10.1016/j.ijrobp.2009.07.1726. Minniti G, Esposito V, Clarke E, et al. Multidose stereotactic radiosurgery (9 Gy _ 3) of the postoperative resection cavity for treatment of large brain metastases. Int J Radiat Oncol Biol Phys 2013;86:623e9. https://doi.org/ 10.1016/j.ijrobp.2013.03.037. Blomgren H, Lax I, Naslund I, Svanstrom R. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients. Acta Oncol 1995;34:861e70. Amersi FF, McElrath-Garza A, Ahmad A, et al. Long term survival after

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

65

radiofrequency ablation of complex unresectable liver tumors. Arch Surg (Chicago Ill, 1960) 2006;141(6):581e7. https://doi.org/10.1001/archsurg.141.6.581. discussion 587-588. Lubrano J, Roman H, Tarrab S, et al. Liver resection for breast cancer metastasis: does it improve survival? Surg Today 2008;38(4):293e9. https:// doi.org/10.1007/s00595-007-3617-2. Martinez SR, Young SE, Giuliano AE, et al. The utility of estrogen receptor, progesterone receptor, and Her2/neu status to predict survival in patients undergoing hepatic resection for breast cancer metastasis. Am J Surg 2006;191(2):281e3. https://doi.org/10.1016/j.amjsurg.2005.08.030. Zegarac M, Nikolic S, Gavrilovic D, et al. Prognostic factors for longer disease free survival and overall survival after surgical resection of isolated liver metastases from breast cancer. J BUON 2013;18(4):859e65. Yamada Y, Cox BW, Zelefsky MJ, et al. An Analysis of prognostic factors for local control of malignant spine tumors treated with spine radiosurgery. Int J Radiat Oncol Biol Phys 2011;81:S132e3. Greco C, Zelefsky MJ, Lovelock M, et al. Predictors of local control after singledose stereotactic image-guided intensity modulated radiotherapy for extracranial metastases. Int J Radiat Oncol Biol Phys 2011;79(4):1151e7. https://doi.org/10.1016/j.ijrobp.2009.12.038. Gerszten PC, Burton SA, Ozhasoglu C, et al. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine 2007;32(2):193e9. https://doi.org/10.1097/01.brs.0000251863.76595.a2. JAN. Gerszten PC, Burton SA, Welch WC, et al. Single-fraction radiosurgery for the treatment of spinal breast metastases. Cancer 2005;104:2244e54. https:// doi.org/10.1002/cncr.21467. Greco C, Pares O, Pimentel N, et al. Spinal metastases: from conventional fractionated radiotherapy to single-dose SBRT. Rep Practical Oncol Radiother 2015;2(0):454e63. https://doi.org/10.1016/j.rpor.2015.03.004. Greco C, Fuks Z, Kim B, Larson S, Yamada Y, Zelefsky M. Post-treatment F-18 FDG-PET standardized uptake value(SUV) predicts local control following high-dosesingle-fraction IGRT. Int J Radiat Oncol Biol Phys 2009;75:S535e6. Diaz-Canton EA, Valero V, Rahman Z, et al. Clinical course of breast cancer patients with metastases confined to the lungs treated with chemotherapy. The University of Texas M.D. Anderson Cancer Center experience and review of the literature. Ann Oncol 1998;9:413e8. Rusthoven KE, Kavanagh BD, Burri SH, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases. J Clin Oncol 2009;27:1579e84. https://doi.org/10.1200/JCO.2008.19.6386. Friedel G, Pastorino U, Ginsberg RJ, et al. Results of lung metastasectomy from breast cancer: prognostic criteria on the basis of 467 cases of the International Registry of Lung Metastases. Eur J Cardio Thorac Surg 2002;22(3): 335e44. Meimarakis G, Ruttinger D, Stemmler J, et al. Prolonged overall survival after pulmonary metastasectomy in patients with breast cancer. Ann Thorac Surg 2013;95(4):1170e80. https://doi.org/10.1016/j.athoracsur.2012.11.043. Vlastos G, Smith DL, Singletary SE, et al. Long-term survival after an aggressive surgical approach in patients with breast cancer hepatic metastases. Ann Surg Oncol 2004;11(9):869e74. https://doi.org/10.1245/ ASO.2004.01.007. Chen F, Fujinaga T, Sato K, et al. Clinical features of clinical resection for pulmonary metastases from breast cancer. Eur J Surg Oncol 2009;35(4): 393e7. https://doi.org/10.1016/j.ejso.2008.05.005. Kycler W, Laski P. Surgical approach to pulmonary metastases from breast cancer. Breast J 2012;18(1):52e7. https://doi.org/10.1111/j.15244741.2011.01176.x. Atalay G, Biganzoli L, Renard F, et al. Clinical outcome of breast cancer patients with liver metastases alone in the anthracycline-taxane era: a retrospective analysis of two prospective, randomised metastatic breast cancer trials. Eur J Cancer 2003;39:2439e49. Duan XF, Dong NN, Li TZQ. The prognostic analysis of clinical breast cancer subtypes among patients with liver metastases from breast cancer. Int J Clin Oncol 2013;18:26e32. https://doi.org/10.1007/s10147-011-0336-x. Scorsetti M, Franceschini D, De Rose F, et al. The role of SBRT in oligometastatic patients with liver metastases from breast cancer. Rep Practical Oncol Radiother 2017;22:163e9. Selzner M, Morse MA, Vredenburgh JJ, Meyers WC, Clavien PA. Liver metastases from breast cancer: long-term survival after curative resection. Surgery 2000;127:383e9. Pocard M, Pouillart P, Asselain B, Falcou MC, Salmon RJ. Hepatic resection for breast cancer metastases: results and prognosis (65 cases). Ann Chir 2001;126:413e20.  M, Furlan C, Polesel J, et al. Radical radiation therapy for oligometaTrovo static breast cancer: results of a prospective phase II trial. Radiother Oncol 2018;126:177e80. https://doi.org/10.1016/j.radonc.2017.08.032. Soffietti R, Kocher M, Abacioglu UM, et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-oflife results. J Clin Oncol 2013;31:65e72. https://doi.org/10.1200/ JCO.2011.41.0639. Hahn C, Kavanagh B, Bhatnagar A, et al. Choosing wisely: the American society for radiation Oncology's top 5 list. Pract Radiat Oncol 2014;4:349e55. https://doi.org/10.1016/j.prro.2014.06.003.

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[98] Fogarty GB, Hong A, Gondi V, et al. Debate: adjuvant whole brain radiotherapy or not? More data is the wiser choice. BMC Cancer 2016;16:372. https://doi.org/10.1186/s12885-016-2433-8. [99] Lawrence YR, Li XA, Naqa IE, Hahn CA, Marks LB, Merchant TE, et al. Radiation dose-volume effects in the brain. Int J Radiat Oncol Biol Phys 2010;76(3 Suppl.):S20e7. https://doi.org/10.1016/j.ijrobp.2009.02.091. [100] Sneed PK, Mendez J, Vemer-van den Hoek JG, Seymour ZA, Ma L, Molinaro AM, et al. Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course and risk factors. J Neurosurg 2015;123(2):373e86. https://doi.org/10.3171/2014.10.JNS141610. [101] Brown PD, Ballmann KV, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC$3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 2017;18:1049e60. https://doi.org/10.1016/ S1470-2045(17)30441-2. [102] Almendro V, Kim HJ, Cheng YK, et al. Genetic and phenotypic diversity in breast tumor metastases. Cancer Res March 1, 2014;74(5). https://doi.org/ 10.1158/0008-5472.CAN-13-2357-T. [103] Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol 2009;10:718e26. https://doi.org/10.1016/S1470-2045(09)70082-8. [104] Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 2005;11:728e34. [105] Pilones KA, Kawashima N, Yang AM, Babb JS, Formenti SC, Demaria S. Invariant natural killer T cells regulate breast cancer response to radiation and CTLA-4 blockade. Clin Cancer Res 2009;15:597e606. https://doi.org/ 10.1158/1078-0432.CCR-08-1277. [106] Verbrugge I, Hagekyriakou J, Sharp LL, et al. Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res 2012;72:3163e74. https://doi.org/ 10.1158/0008-5472.CAN-12-0210. [107] Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014;124: 687e95. https://doi.org/10.1172/JCI67313. [108] Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent antiprogrammed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010;28(19):3167e75. https://doi.org/10.1200/JCO.2009.26.7609. [109] Sibaud V, David I, Lamant L, et al. Acute skin reaction suggestive of pembrolizumab-induced radiosensitization. Melanoma Res 2015;25(6): 555e8. https://doi.org/10.1097/CMR.0000000000000191. [110] Crittenden M, Kohrt H, Levy R, et al. Current clinical trials testing combinations of immunotherapy and radiation. Semin Radiat Oncol 2015;25(1): 54e64. https://doi.org/10.1016/j.semradonc.2014.07.003. [111] Aneja S, Pratiwadi RR, Yu JB. Hypofractionated radiation therapy for prostate cancer: risks and potential benefits in a fiscally conservative health care system. Oncology (Williston Park) 2012;26(6):512e8. [112] Yabroff KR, Davis WW, Lamont EB, et al. Patient time costs associated with cancer care. J Natl Cancer Inst 2007;99:14e23. https://doi.org/10.1093/jnci/ djk001. [113] Sullivan R, Peppercorn J, SikoraK, et al. Delivering affordable cancer care in high-income countries. Lancet Oncol 2011;12:933e80. https://doi.org/ 10.1016/S1470-2045(11)70141-3. [114] Bijlani A, Aguzzi G, Schaal DW, et al. Stereotactic radiosurgery and stereotactic body radiation therapy cost-effectiveness results. Front Oncol 2013;3:

1e9. https://doi.org/10.3389/fonc.2013.00077. [115] Sher DJ, Wee JO, Punglia RS. Cost-effectiveness analysis of stereotactic body radiotherapy and radiofrequency ablation for medically inoperable, earlystage non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81: e767e74. https://doi.org/10.1016/j.ijrobp.2010.10.074. [116] Lester-Coll NH, Sher DJ. Cost-effectiveness of stereotactic radiosurgery and stereotactic body radiation therapy: a critical review. Curr Oncol Rep 2017;19:41. https://doi.org/10.1007/s11912-017-0599-0. [117] Kased N, Binder DK, McDermott MW, et al. Gamma-Knife radiosurgery for brain metastases from primary breast cancer. IJROBP 2009;75(4):1132e40. https://doi.org/10.1016/j.ijrobp.2008.12.031. [118] Gagnon GJ, Henderson FC, Gehan EA, et al. CynerKnife radiosurgery for breast cancer spine metastases. Cancer October 15, 2007;110(8). https:// doi.org/10.1002/cncr.22977. [119] Scorsetti M, Franceschini D, De Rose F, et al. Stereotactic body radiation therapy: a promising chance for oligometastatic breast cancer. Breast 2016;26:11e7. https://doi.org/10.1016/j.breast.2015.12.002. [120] Combs SE, Shultz-Ertner D, Thilmann C, et al. Treatment of cerebral metastases from breast cancer with stereotactic radiosurgery. Strahlenther Onkol 2004;9:590e6. https://doi.org/10.1007/s00066-004-1299-x. [121] Muacevic A, Kreth FW, Tonn JC, et al. Stereotactic radiosurgery for multiple brain metastases from breast carcinoma. Cancer 2004;100(8):1705e11. https://doi.org/10.1002/cncr.20167. [122] Golden DW, Lamborn KR, MCDermott RW, et al. Prognostic factors and grading systems for overall survival in patients treated with radiosurgery for brain metastases: variation by primary site. J Neurosurg 2008;109:77e86. [123] Matsunaga S, Shuto T, Kawahara N, et al. Gamma Knife surgery for metastatic brain tumors from primary breast cancer: treatment indication based on number of tumors and breast cancer phenotype. J Neurosurg 2010;113: 65e72. [124] Kondziolka D, Kano H, Harrison GL, et al. Stereotactic radiosurgery as primary and salvage treatment for brain metastases from breast cancer. Clin Article J Neurosurg 2011;114(3):792e800. https://doi.org/10.3171/ 2010.8.JNS10461. [125] Caballero JA, Sneed PK, Lamborn KR, et al. Prognostic factors for survival in patients treated with stereotactic radiosurgery for recurrent brain metastases after prior whole brain radiotherapy. Int J Radiat Oncol Biol Phys 2012;83(1):303e9. https://doi.org/10.1016/j.ijrobp.2011.06.1987. [126] Dyer MA, Kelly PJ, Chen YH, et al. Importance of extracranial disease status and tumor subtype for patients undergoing radiosurgery for breast cancer brain metastases. Int J Radiat Oncol Biol Phys 2012;83(4):e479e86. https:// doi.org/10.1016/j.ijrobp.2012.01.054. [127] Yamamoto M, Kawabe T, Higuchi Y, et al. Validity of three recently proposed prognostic grading indexes for breast cancer patients with radiosurgically treated brain metastases. Int J Radiat Oncol Biol Phys 2012;84(5):1110e5. https://doi.org/10.1016/j.ijrobp.2012.02.040. [128] Yomo S, Hayashi M, Cho N. Impacts of HER2-overexpression and molecular targeting therapy on the efficacy of stereotactic radiosurgery for brain metastases from breast cancer. J Neuro Oncol 2013;112:199e207. https:// doi.org/10.1007/s11060-013-1046-1. [129] Geraud A, Xu HP, Beuzeboc P, et al. Preliminary experience of the concurrent use of radiosvurgery and T-DM1 for brain metastases in HER2-positive metastatic breast cancer. J Neuro Oncol 2017;131:69e72. https://doi.org/ 10.1007/s11060-016-2265-z.