Clinical Outcomes of Patients with Metastatic Breast Cancer treated with Hypo-Fractionated Liver Radiotherapy

Clinical Outcomes of Patients with Metastatic Breast Cancer treated with Hypo-Fractionated Liver Radiotherapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical Outcomes of Patients with Metastatic Breast Cancer treated with Hypo-Fractionated Liver Radiotherapy Melinda MUSHONGA, Joelle Helou, Jessica Weiss, Laura Dawson, Jelena Lukovic, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2234222/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction Growing data support the safe and efficacious use of ablative radiotherapy in the setting of liver metastases, with some studies suggesting that patients with metastatic breast cancer (MBCa) do better than patients with metastases from other cancers. This study aims to retrospectively review clinical outcomes of patients with MBCa following liver radiotherapy (RT). Materials and Methods Patients with MBCa who received liver hypo fractionated ablative RT between 2004 – 2020 were classified according to metastatic classification and treatment intent (i.e., oligo-metastatic (OM) or oligo-progressive (OP)). Demographics, disease characteristics and treatment characteristics were collated. Primary outcome was local control (LC) of treated metastases. Secondary outcomes included overall survival (OS), progression-free survival (PFS), and time to next line systemic therapy (ST), analyzed by univariate (UVA) and multi-variable analysis (MVA). Results Thirty MBCa patients with 50 liver metastases treated with 5 – 10 fraction ablative intent RT were identified for analysis. Median follow-up was 14.6 months (range 0.9 - 156.2 months). Mean age was 55.6 years (range 32.1 - 79.3 years); 53% were ER+/HER2-ve and 33% HER2+ve. Class of metastatic disease was described as – induced (12 patients, 40%), repeat (15 patients, 50%) and de novo (3 patients, 10%) (1 synchronous, 2 metachronous). Indication of treatment was OP (73%) and OM (27%). Median size of treated liver metastases (LM) was 3.1 cm (range 1cm – 8.8 cm) and the median dose delivered was 40Gy (range 30Gy-60Gy). 1 and 3-year LC rates were 100%. Median OS was 57.7-months with size of treated liver metastases predictive of overall survival (HR 1.35, p=0.023) on UVA. Median time to progression post treatment was 4.8 months (0.8 – 114.7). Patients with induced OMD had a significantly higher rate of progression (HR 4.77, p=0.01) on UVA compared to others, which trended to significance on MVA (HR 3.23, p=0.051). Conclusion Hypo-fractionated ablative liver RT in patients with MBCa provides safe, tolerable treatment with excellent LC. Further studies assessing the impact, ideal sequencing, and indications of RT in each metastatic class in MBCa are required. Liver metastasis Breast cancer Ablative Radiotherapy Introduction The liver is the third most prevalent site of metastatic spread in breast cancer, preceded by lung and bone 1 and is associated with a median survival of 2 to 3 years 2 and a 5-year overall survival (OS) rate of only 8.5% 1 . Advancements in cross-sectional and functional imaging have allowed for improved identification of patients with limited metastatic disease. The literature describing outcomes following local treatment of limited metastatic lesions reports mixed clinical outcomes 3 , 4 , 5 . Some studies suggest breast cancer patients with oligo-metastatic disease benefit more from the use of ablative radiotherapy in comparison to other primary cancers 6 , 7 , whilst two recent breast specific studies suggest the contrary. The European Society Radiation Oncology (ESTRO)/European Organization of Research and Treatment of Cancer (EORTC) metastatic classification system has defined metastatic groups and this will likely aid in streamlining clinical indications for treatment to better define the role of ablative RT in the metastatic setting 8 , 9 . The objective of this retrospective cohort study is to describe the clinical outcomes of patients with metastatic breast cancer (MBCa), who received hypo-fractionated liver radiotherapy (RT), and the impact of metastatic classification and treatment indication. Methods Metastatic breast cancer patients with liver metastases who received liver hypo-fractionated RT of up to 10 fractions between 2004 and 2020 were identified as part of a research ethics board approved retrospective study. Metastatic disease was classified as per the ESTRO/EORTC classification system 8 . Indication of treatment was classified as oligo-metastatic (OM; patients with limited metastatic disease with all metastases receiving ablative therapy) or oligo-progressive disease (OP; patients with widespread metastatic disease in the setting of limited progressing lesions). Liver radiotherapy planning has been discussed in previous publications 10 , 11 . Data were collected from the Electronic Patient Records and RT information system ( e.g Mosaiq – Elekta, Stockholm, Sweden). The following parameters were recorded: patient demographics, pathology, details on pre and post RT systemic therapy, RT treatment details i.e., number of treated lesions, total biologically effective dose (BED) of prescribed dose and number of fractions. When they were multiple targets, radiotherapy treatment details to the largest lesion were reported. An α/β ratio of 3 for local control, generated and informed by the START Pilot, START A, FAST and FAST FORWARD trials, was used for the biological equivalent dose (BED ) calculation 12 , 13 , 14 . Information on acute toxicities was collected and toxicity scoring was described as per the National Cancer Institute- Common Terminology Criteria for Adverse Events version 4 (CTCAE) 15 . Outcomes And Statistical Analysis The primary outcome was local control (LC) of the treated metastatic liver lesion measured from the last day of RT. Local failure was defined as enlargement of the treated lesion measured on at least two consecutive computed tomography (CT) scans post radiotherapy within the planning target volume (PTV). The date of progression was taken as the day the second scan was completed from the last CT scan with stable findings as reported by the reporting radiologist. Follow-up imaging overall was performed as per institutional guidelines at 8–12 weeks post RT treatment and every 3–6 months thereafter and reported by a gastrointestinal radiologist. Secondary outcomes included progression-free survival (PFS) - defined as time to progression outside the treated field (i.e. in the liver but outside of the PTV, regional nodes or distant sites), OS, and time to second line systemic therapy post liver hypo-fractionated - RT. OS was calculated from completion of RT to the date of death or censored at last follow up, and PFS was calculated to the date of any progression. For both time points, the hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using Cox proportional Hazards model. Time to second line systemic therapy post RT was measured from time of initiation of a second line systemic therapy from the time the patient was switched from the ST the patient was on after RT and was estimated using the cumulative incidence function accounting for the competing risk of death. Univariate analysis (UVA) and multi-variable analysis (MVA) were performed on OS, PFS and time to change of systemic therapy. Factors included were, molecular subtype, treatment intent (OM/OP), EORTC classification (repeat; induced; de novo), lines of systemic therapy pre ablative liver RT, size of largest metastatic liver lesion and BED 3 ( 100). All significant variables on UVA were included in MVA, with additional variables based on clinical judgement added thereafter. Statistical analysis was performed using the software package R v 3.4. 2.. In the analysis, a p value of < 0.05 was considered significant. Results Between June 2004 and October 2020, 30 patients with 50 liver metastases were treated with hypo-fractionated RT. The median age was 55.6 years (range 32.1–79.3), with 21 (70%) patients having metastatic liver only disease at time of RT. Computed tomography was used to stage 93% of patients, with only 2 patients undergoing Magnetic Resonance with primovist imaging. The most common molecular subtype was Estrogen receptor (ER) positive (+ ve)/Her 2-receptor negative (–ve) (17, 57%). As per the EORTC classification system, 12 (40%) patients had induced, 15 (50%) repeat and 3 (10%) de novo (1 synchronous, 2 metachronous) oligo-metastatic disease (OMD). Oligo-progression (OP) of the liver metastases was the indication for treatment in 22 (73%) patients. Median diameter of the treated liver metastases was 3.15 cm (interquartile range {IQR} of 2.4–5.1) and median prescribed BED delivered was 122 Gy 3 (IQR of 97.9–174.3) in 5–10 fractions. The most common number of fractions was 5 (14 patients), with 13 patients treated in 6 fractions. Only 3 patients (10%) received a 10 fraction RT regimen (median BED 3 112.5Gy). (Table 1 ) Table 1 Patient, disease, and treatment characteristics Covariate N = 30 Age Median, years (range) 55.6 (32.1–79.3) Histology Invasive ductal carcinoma Invasive lobular carcinoma Others 23 (77) 4 (13) 3 (10) Molecular subtype ER + ve /Her 2 -ve ER + ve/Her 2 + ve ER-ve/ Her 2 + ve ER-ve/ Her 2 -ve 17 (57) 7 (23) 2 (7) 4 (13) Number of initial metastatic sites 1 (Liver only) 2 3 21 (70) 6 (20) 3 (10) Time from primary diagnosis to ablative radiotherapy to liver lesions Median, months (Q1 – Q3) 371(18.5–73.3) Number of treated liver metastases Median (range) 1(1–5) Number of treated liver metastases (N = 50) 1 2 3 4 5 15 7 4 1 1 Metastatic classification Induced OM Repeat OM De novo OM 12 (40%) 15 (50%) 3 (10%) Lines of systemic therapy pre ablative radiotherapy to liver lesions Median (range) 2 (0–6) Initial diameter of largest metastatic lesion for treatment (cm) Median (Q1 - Q3) 3.15 (2.4–5.1) Treatment Indication OP OM 22 (73) 8 (27) Systemic therapy post ablative radiotherapy to liver lesions Yes No Missing 28 (93) 1 1 BED 3 Median (Q1 - Q3) 122.1 (97.9–174.3) Number of fractions Median (Range) 6 (5–10) Number of fractions 5 6 10 15 (50) 12 (40) 3 (10) Acronyms – ER - Estrogen; OM - Oligometastases; OP - Oligoprogression; BED - biological equivalent dose; Outcomes Post Hypo Fractionated Rt Treatment Median follow-up for the entire cohort was 14.6 (range 0.9–156.2) months. The LC of treated metastatic lesions at 1 and 3years was 100%. Only one local failure (patient classified as induced OMD receiving treatment for OP) was identified at 40 months post RT. This patient had ER/PR negative, HER2 positive breast cancer, they received a BED 3 of 93 Gy in 10 fractions and were still alive at the time of last follow up (13-years post RT). Median OS for the entire cohort was 57.7 months (Range 0.9–156.2 months). One year and two-year survival was 89% and 63% respectively. Larger size, size greater than 3 cm (median Q1, Q3; 2.4, 5.1), of treated liver metastatic lesion was the only variable predictive of worse survival (HR 1.35 [95%CI: 1.04–1.75] p = 0.023) on UVA, however it was not significant on MVA (p = 0.066). (Table 2 ) Table 2 Univariate and Multivariable Analysis of Overall Survival Variable Overall Survival Univariate Analysis Multivariable Analysis HR 95% CI p-value HR 95% CI p-value Molecular subtype (ER + ve /Her 2 -ve Others) 1.03 0.33–3.22 0.96 Treatment Intent OM OP 4.59 0.99–21.37 0.052 4.32 0.97–21.58 0.074 EORTC classification Repeat Induced De Novo Reference 2.04 2.25 0.56–7.45 0.42–11.94 0.46* Lines of systemic therapy pre ablative liver RT 1.36 0.93–1.98 0.11 0.92 0.58–1.45 0.72 Size of largest metastatic liver lesion 1.35 1.04–1.75 0.023 1.34 0.98–1.84 0.066 BED 3 100 1.27 0.27–6.09 0.76 Acronyms – ER - Estrogen; EORTC-European Organization for Research and Treatment of Cancer; OM - Oligometastases; OP - Oligoprogression; RT - Radiotherapy; BED - biological equivalent dose; HR - Hazard ratio; CI - Confidence Interval. *global p-value Half of patients developed disease progression outside of the treated liver metastases, with a median time to progression post RT of 4.8 (range 0.8–114.7) months. The majority were patients with induced OMD (11 patients; 73%), followed by repeat (3 patients; 20%) and de novo OMD (1 patient; 7%). Oligo-progression was the most common indication for liver RT in patients who subsequently developed further disease progression (80%). The most common sites of distant failure were lung 33% (5/15) and bone 27% (4/15). Other sites included brain, lymph nodes and omental metastases. Classification of metastases and indication of treatment were the only variables significantly associated with disease progression on UVA. Patients with induced OMD had a statistically significant higher rate of progression (HR 4.77, p = 0.01) on UVA compared to others, which trended to significance on MVA (HR 3.23, p = 0.051). Disease progression outside of the treated liver was more likely in patients where the indication of treatment was oligo-progression (HR 3.72, p = 0.044). (Tables 2 and 3 ) Table 3 Univariate and Multivariable Analysis of Progression Free Survival Variable Progression Free Survival Univariate Analysis Multivariable Analysis HR 95% CI p-value HR 95% CI p-value Molecular subtype (ER + ve /Her 2 -ve Others) 0.91 0.35–2.36 0.84 Treatment Intent OM OP 3.72 1.04–13.3 0.044 3.27 0.67–16.01 0.14 EORTC classification Repeat Induced De Novo reference 4.77 3.47 1.44–15.80 0.61–19.88 0.022 * reference 3.23 6.75 0.95–10.96 1–45.38 0.051* Lines of systemic therapy pre ablative liver RT 1.29 0.95–1.75 0.10 1.14 0.76–1.69 0.53 Size of largest metastatic liver lesion 1.14 0.93–1.39 0.21 BED 3 100 0.39 0.14–1.06 0.066 Acronyms – ER - Estrogen; OM - Oligometastases; OP - Oligoprogression; RT - Radiotherapy; BED - biological equivalent dose; HR - Hazard ratio; CI - Confidence Interval. *global p-value Pre-hypo Fractionated Rt And Post Hypo Fractionated Rt Systemic Treatment All patients, but one, received some form of systemic therapy from initial diagnosis to receipt of ablative liver RT (Table 1 ). The median lines of pre-ablative RT systemic therapy received by all patients were 2 (range 0–6). Seventeen patients (56%) were switched to next line systemic therapy post liver RT, i.e. 10 patients at different points of documented disease progression and 7 in the immediate period after receipt of RT without indication of progression. The median time to second line ST after RT was 9.9 (range 1–114) months. For patients initiated on second line systemic therapy at disease progression having continued pre-RT systemic therapy, the median time was 5.4 (range 2–114) months in comparison with 19.1 (4.4–26.4) months for patients initiated on another ST at time of RT and second line at time of disease progression. No variable on UVA was predictive of switching to second line systemic therapy post RT as per Table 4 . Table 4 Univariate Analysis of Time to Next Line Systemic Therapy Variable Time to Next Line Systemic Therapy Univariate Analysis HR 95% CI p-value Molecular subtype ER + ve /Her 2 -ve Others 0.85 0.32–2.23 0.74 EORTC classification Repeat Induced De Novo Reference 1.25 1.23 0.45–3.53 0.46–3.26 0.88* Lines of systemic therapy pre ablative liver RT 1.27 0.99–1.64 0.057 Size of largest metastatic liver lesion 1.17 0.95–1.44 0.15 BED 3 100 0.47 0.12–1.88 0.29 Treatment intent OM OP Reference 1.27 (0.51,3.17) 0.6 Acronyms – ER - Estrogen; OM - Oligometastases; OP - Oligoprogression; RT - Radiotherapy; BED - biological equivalent dose; HR - Hazard ratio; CI - Confidence Interval. *global p-value Acute And Late Toxicities Acute grade 1 and 2 toxicities were reported in 20/30 (66%), with the most common acute toxicities of nausea (68%) and fatigue (61%) reported. One patient developed a CTCAE (version 4.0) grade 3 RT related gastric ulcer within 3 months of treatment confirmed by endoscopy after presenting with hematemesis. The patient had two liver metastases treated. One of the lesions was in segment 3 of the liver adjacent to the stomach and was prescribed 30Gy in 5 fractions. The smaller second lesion in segment 6 was prescribed 40Gy in 5 fractions. An abdominal compression system was used for motion management including image guidance for each treatment session. They received prophylactic proton pump inhibitors and anti-nausea medication for the duration of the treatment as per standard institutional practice. The maximum dose to the stomach was 31Gy and a corresponding mean of 12Gy. Gastritis was managed by medication alone with a proton pump inhibitor and the patient recovered clinically on next follow up. No late CTCAE grade 2 or higher radiotherapy related toxicities were recorded. Discussion Hypo-fractionated liver RT, regardless of metastatic classification, resulted in excellent LC of treated metastatic liver lesions: 1 and 3- year LC in our cohort was 100%. These outcomes are consistent with current literature describing patients with metastatic breast cancer treated with liver SBRT, reporting 1 and 2-year LC rates of 88–100% and 75–88%, respectively 16 – 18 . One and two-year overall survival rates of 89% and 63% described in this study were also similar to that reported in the literature 16 , 17 , 18 . The only significant variable associated with survival was the size of the treated liver metastases (> 3cm), with larger sized metastases associated with worse survival. Larger metastases have previously been associated with poorer LC in patients with metastatic breast cancer receiving curative intent SBRT 19 . This has been attributed to an increased risk of micro-metastatic disease 20 , notable in larger sized lesions likely resulting in distant failure hence poor survival. About half of patients described developed early disease progression, with a median PFS of 4.8 months. A difference in PFS was seen between metastatic classes. There is a paucity of clinical data describing breast cancer patient outcomes as per ESTRO/EORTC classification system; induced oligo progression has been shown to be associated with worse survival in non-breast cancer patients. 21 . Tan et al retrospectively described a cohort of 120 patients with metastatic breast cancer treated with SBRT to various anatomical sites (24 patients had liver SBRT), noting a difference in OS and PFS in favor of patients with OMD compared to OP disease 22 . These findings suggest that differences in survival outcomes may exists based on classification of metastatic disease. In the setting of patients with induced OMD, in our study, these had a higher rate of progression compared to patients with repeat or de novo OMD. The recent phase IIR NRG BR002 trial 5 included non-classified oligo-metastatic breast cancer patients defined as patients with 4 or less extra-cranial metastatic lesions, required to have a controlled primary and had to be on standard of care ST for ≤ 12 months prior to enrolment. The study compared ablative therapy (93% SBRT, 7% surgery) to all lesions with ST versus ST alone, however reporting a 2-year PFS of 46.8% 5 with no difference in median PFS in patients who received the combination arm compared to ST alone (19.5 vs 23 months, p = 0.92). By EORTC classification, this cohort, would be classified as having de novo metastatic disease – either synchronous or metachronous setting. These findings highlight the need for trials with pre-defined subgroups to inform which cohort of breast cancer patients may benefit from ablative therapy in the setting of limited metastases and further inform sequencing with ST. Oligo-progression was the treatment indication for most patients described in this study (73%). This group of patients is commonly defined as having widespread metastatic disease with a limited number of metastases progressing on systemic therapy and are less well studied with unanswered questions on the right timing to initiate systemic therapy 23 . The CURB study 24 a prospective randomized breast cancer study, treated patients with ≤ 5 progressing metastatic lesions with standard of care ST with or without SBRT. There was no difference in median PFS between patients who received SBRT (n = 24) and those who did not (n = 23) (18 vs 19 weeks, p = 0.47). One reason may be that patients with OP disease are often heavily pretreated with systemic therapies and harbor radioresistant clones resulting in inferior LC post ablative RT 25 . Patients with OP in our study received more lines of pre-RT systemic therapy compared to patients with OMD, but this did not appear to affect LC rates. A common clinical indication for ablative RT in patients with OP disease is to delay start of next line ST, especially in the setting of limited lines of ST. Interestingly in this cohort, some patients were switched to another ST in the immediate period after RT, and had a longer interval of time to switch to second line ST post RT compared to those switched at time of progression after continuing on pre RT systemic therapy. These differences were however not analyzed further for statistical significance and warrant to be further studied in a prospective setting to inform appropriate timing of switching to next line ST when ablative RT is considered in the treatment plan. Breast cancer is recognized generally as being radiosensitive, however there is limited data on the impact of molecular subtypes. With the recently updated TNM staging accounting for molecular classification, it has not yet been established if radiotherapy should be altered to account for the potential variation in biology. Evidence supporting dose escalation in the setting of K-RAS mutant colorectal 26 – 30 cancer suggests intrinsic biology matters. Neither molecular subtype or BED > 100 Gy 3 impacted primary or secondary outcomes in this retrospective review. It is poorly understood how different molecular subtypes respond to RT 31 . Yard et al, described breast cancer cell lines with elevated ERBB2 , being associated with radiation resistance prior to Her 2 targeted systemic therapy introduction 32 . Subsequent studies have however shown that trastuzumab, sensitizes breast cancer cells to radiation by enhancing radiation induced apoptosis conferring radiosensitivity which ultimately translates to superior LC 33 . The small subset of Her 2 positive patients precluded a meaningful analysis to compare with findings from precedent studies described. Radiation dose is an established predictor of local control, 34 and in this study, local control was excellent regardless of dose received. This seemingly reaffirms the radiosensitive nature of breast cancer which is increasingly being described. However, a study by Klement et al who investigated tumor control in patients with liver metastases receiving SBRT found that compared with other histology, breast cancer had the strongest relationship between LC and largest BED (using an alpha/beta 10) 25 . Conversely, Tan H et al ,found no association between BED (using an alpha/beta 3) or molecular subtype and local control in breast cancer patients receiving SBRT to extracranial metastases in varying anatomical locations similar to findings in this liver specific study. 22 Due to its retrospective nature, this study has limitations which include the presence of missing data, reporting bias, selection bias and confounders such as the use of pre- and post- ablation systemic therapy and evolving systemic treatment options during the study period. Also, due to the long period of time over which patients were treated, there have been changes to how patients are managed, such as radiological staging (CT vs MR) and systemic therapies. However, several interesting questions have been brought forward regarding the evolution of the integration of ablative RT in the setting of metastatic breast cancer. It is apparent, on literature review, there is a paucity of data describing patients with breast cancer according to the different classes of metastatic disease, indications of treatment, systemic therapies and molecular subtype 35 . Such variables should guide future studies with the aim to better prognosticate patients 36 who will likely benefit from ablative radiotherapy and optimum sequencing with evolving modern systemic therapies 37 , aiding clinician and patient decision making. Conclusion Hypo-fractionated ablative liver radiotherapy in patients with MBCa provides safe, tolerable treatment with excellent LC. Further studies are needed to identify patients with MBCa according to metastatic class who might benefit from ablative RT. Declarations Acknowledgement Dr Elizabeth Guimond and Tim Craig who both had no role in study design, data collection, data analysis, data interpretation, or writing of the report, but guided in clarifying technical details on treatment information. Conflict of Interest No pertinent conflict of interest to declare. Ethics Approval This study received institutional approval. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References Ji L et al (2021) Risk and prognostic factors of breast cancer with liver metastases. BMC Cancer 21:1–15 Rashid NS, Grible JM, Clevenger CV, Harrell JC (2021) Breast cancer Liver metastases: Current and future treatment approaches. 38:263–277 Fabian A, Pyschny F, Krug D (2019) Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. 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MUSHONGA","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYFAC5gYgcUCOgYGHaC2MYC3GpGtJbCBai257Y+tmnj930jccP3vwwQcGOzndBgJazM4cbLvN2/Ysd8OZvGTDGQzJxmYHCGm5kQjU0nA4d8OBHDNpHqALtxHUcv9h222eP4fTDc6/IVbLDUagFrbDCQY3iLblTGLbzblthw1n3nhjbDjDgBi/HD987MabP4fl+c7nGD74UGEnR1ALHCiAVRoQqxwE5BtIUT0KRsEoGAUjCgAAux9MCeBD/XgAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-3983-4892","institution":"Sunnybrook Health Sciences Centre Odette Cancer Centre","correspondingAuthor":true,"prefix":"","firstName":"Melinda","middleName":"","lastName":"MUSHONGA","suffix":""},{"id":149579205,"identity":"5f65e4f0-3032-402c-ba63-e0abd4ed66cc","order_by":1,"name":"Joelle Helou","email":"","orcid":"","institution":"Princess Margaret Hospital: Princess Margaret Hospital Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"Joelle","middleName":"","lastName":"Helou","suffix":""},{"id":149579206,"identity":"18f7637a-9b66-4883-9bd6-491895351a35","order_by":2,"name":"Jessica Weiss","email":"","orcid":"","institution":"Princess Margaret Hospital: Princess Margaret Hospital Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"Jessica","middleName":"","lastName":"Weiss","suffix":""},{"id":149579207,"identity":"d5d792af-6528-4d59-b01f-5298931682c7","order_by":3,"name":"Laura Dawson","email":"","orcid":"","institution":"Princess Margaret Hospital: Princess Margaret Hospital Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Dawson","suffix":""},{"id":149579208,"identity":"93e60818-c5f3-4613-9ed5-41ec9511f6c2","order_by":4,"name":"Jelena Lukovic","email":"","orcid":"","institution":"Princess Margaret Hospital: Princess Margaret Hospital Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"Jelena","middleName":"","lastName":"Lukovic","suffix":""},{"id":149579209,"identity":"8d34708c-6858-43d5-aed2-391c80573c5d","order_by":5,"name":"Rebecca Wong","email":"","orcid":"","institution":"Princess Margaret Hospital: Princess Margaret Hospital Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"Rebecca","middleName":"","lastName":"Wong","suffix":""},{"id":149579210,"identity":"c108fb12-fe42-4f11-874a-1901109170b3","order_by":6,"name":"ALI HOSNI ABDALATY","email":"","orcid":"","institution":"Princess Margaret Hospital: Princess Margaret Hospital Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"ALI","middleName":"HOSNI","lastName":"ABDALATY","suffix":""},{"id":149579211,"identity":"8aff010e-360a-4e70-86c8-d84a28bfb50d","order_by":7,"name":"John Kim","email":"","orcid":"","institution":"Princess Margaret Hospital: Princess Margaret Hospital Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"","lastName":"Kim","suffix":""},{"id":149579212,"identity":"811bb92e-17d9-47eb-93ef-2437f3348e5b","order_by":8,"name":"Anne C Koch","email":"","orcid":"","institution":"Princess Margaret Hospital: Princess Margaret Hospital Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"Anne","middleName":"C","lastName":"Koch","suffix":""},{"id":149579213,"identity":"c3066c95-3cc5-4002-a6e4-b9cb18d8b50a","order_by":9,"name":"Patricia Lindsay","email":"","orcid":"","institution":"Princess Margaret Hospital: Princess Margaret Hospital Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"Patricia","middleName":"","lastName":"Lindsay","suffix":""},{"id":149579214,"identity":"4b097530-42a3-4128-a221-02abb869f115","order_by":10,"name":"Teodor Stanescu","email":"","orcid":"","institution":"Princess Margaret Hospital: Princess Margaret Hospital Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"Teodor","middleName":"","lastName":"Stanescu","suffix":""},{"id":149579215,"identity":"24bd3832-4014-464b-8cba-647dfd130e78","order_by":11,"name":"Khalid Alrabiah","email":"","orcid":"","institution":"Princess Margaret Hospital: Princess Margaret Hospital Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"Khalid","middleName":"","lastName":"Alrabiah","suffix":""},{"id":149579216,"identity":"b41b6661-ed0e-41de-ae12-aa2bd2360290","order_by":12,"name":"Aisling Barry","email":"","orcid":"","institution":"University College Cork","correspondingAuthor":false,"prefix":"","firstName":"Aisling","middleName":"","lastName":"Barry","suffix":""}],"badges":[],"createdAt":"2022-11-03 12:49:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2234222/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2234222/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":29373698,"identity":"92c62c1d-f275-4e38-94db-a7911e3701b1","added_by":"auto","created_at":"2022-11-22 07:11:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":329049,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2234222/v1/6a5ec8db-2d82-4155-b20e-e8627a93f414.pdf"}],"financialInterests":"","formattedTitle":"Clinical Outcomes of Patients with Metastatic Breast Cancer treated with Hypo-Fractionated Liver Radiotherapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe liver is the third most prevalent site of metastatic spread in breast cancer, preceded by lung and bone\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and is associated with a median survival of 2 to 3 years\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e and a 5-year overall survival (OS) rate of only 8.5%\u003csup\u003e1\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAdvancements in cross-sectional and functional imaging have allowed for improved identification of patients with limited metastatic disease. The literature describing outcomes following local treatment of limited metastatic lesions reports mixed clinical outcomes \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Some studies suggest breast cancer patients with oligo-metastatic disease benefit more from the use of ablative radiotherapy in comparison to other primary cancers\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, whilst two recent breast specific studies suggest the contrary. The European Society Radiation Oncology (ESTRO)/European Organization of Research and Treatment of Cancer (EORTC) metastatic classification system has defined metastatic groups and this will likely aid in streamlining clinical indications for treatment to better define the role of ablative RT in the metastatic setting \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe objective of this retrospective cohort study is to describe the clinical outcomes of patients with metastatic breast cancer (MBCa), who received hypo-fractionated liver radiotherapy (RT), and the impact of metastatic classification and treatment indication.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eMetastatic breast cancer patients with liver metastases who received liver hypo-fractionated RT of up to 10 fractions between 2004 and 2020 were identified as part of a research ethics board approved retrospective study. Metastatic disease was classified as per the ESTRO/EORTC classification system \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Indication of treatment was classified as oligo-metastatic (OM; patients with limited metastatic disease with all metastases receiving ablative therapy) or oligo-progressive disease (OP; patients with widespread metastatic disease in the setting of limited progressing lesions). Liver radiotherapy planning has been discussed in previous publications\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eData were collected from the Electronic Patient Records and RT information system ( e.g Mosaiq \u0026ndash; Elekta, Stockholm, Sweden). The following parameters were recorded: patient demographics, pathology, details on pre and post RT systemic therapy, RT treatment details i.e., number of treated lesions, total biologically effective dose (BED) of prescribed dose and number of fractions. When they were multiple targets, radiotherapy treatment details to the largest lesion were reported. An α/β ratio of 3 for local control, generated and informed by the START Pilot, START A, FAST and FAST FORWARD trials, was used for the biological equivalent dose (BED ) calculation\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Information on acute toxicities was collected and toxicity scoring was described as per the National Cancer Institute- Common Terminology Criteria for Adverse Events version 4 (CTCAE) \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eOutcomes And Statistical Analysis\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was local control (LC) of the treated metastatic liver lesion measured from the last day of RT. Local failure was defined as enlargement of the treated lesion measured on at least two consecutive computed tomography (CT) scans post radiotherapy within the planning target volume (PTV). The date of progression was taken as the day the second scan was completed from the last CT scan with stable findings as reported by the reporting radiologist. Follow-up imaging overall was performed as per institutional guidelines at 8\u0026ndash;12 weeks post RT treatment and every 3\u0026ndash;6 months thereafter and reported by a gastrointestinal radiologist. Secondary outcomes included progression-free survival (PFS) - defined as time to progression outside the treated field (i.e. in the liver but outside of the PTV, regional nodes or distant sites), OS, and time to second line systemic therapy post liver hypo-fractionated - RT.\u003c/p\u003e \u003cp\u003eOS was calculated from completion of RT to the date of death or censored at last follow up, and PFS was calculated to the date of any progression. For both time points, the hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using Cox proportional Hazards model. Time to second line systemic therapy post RT was measured from time of initiation of a second line systemic therapy from the time the patient was switched from the ST the patient was on after RT and was estimated using the cumulative incidence function accounting for the competing risk of death. Univariate analysis (UVA) and multi-variable analysis (MVA) were performed on OS, PFS and time to change of systemic therapy. Factors included were, molecular subtype, treatment intent (OM/OP), EORTC classification (repeat; induced; de novo), lines of systemic therapy pre ablative liver RT, size of largest metastatic liver lesion and BED\u003csub\u003e3\u003c/sub\u003e (\u0026lt;\u0026thinsp;100; \u0026gt; 100). All significant variables on UVA were included in MVA, with additional variables based on clinical judgement added thereafter. Statistical analysis was performed using the software package R v 3.4. 2.. In the analysis, a p value of \u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBetween June 2004 and October 2020, 30 patients with 50 liver metastases were treated with hypo-fractionated RT. The median age was 55.6 years (range 32.1\u0026ndash;79.3), with 21 (70%) patients having metastatic liver only disease at time of RT. Computed tomography was used to stage 93% of patients, with only 2 patients undergoing Magnetic Resonance with primovist imaging. The most common molecular subtype was Estrogen receptor (ER) positive (+\u0026thinsp;ve)/Her 2-receptor negative (\u0026ndash;ve) (17, 57%). As per the EORTC classification system, 12 (40%) patients had induced, 15 (50%) repeat and 3 (10%) de novo (1 synchronous, 2 metachronous) oligo-metastatic disease (OMD). Oligo-progression (OP) of the liver metastases was the indication for treatment in 22 (73%) patients. Median diameter of the treated liver metastases was 3.15 cm (interquartile range {IQR} of 2.4\u0026ndash;5.1) and median prescribed BED delivered was 122 Gy\u003csub\u003e3\u003c/sub\u003e (IQR of 97.9\u0026ndash;174.3) in 5\u0026ndash;10 fractions. The most common number of fractions was 5 (14 patients), with 13 patients treated in 6 fractions. Only 3 patients (10%) received a 10 fraction RT regimen (median BED\u003csub\u003e3\u003c/sub\u003e 112.5Gy). (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient, disease, and treatment characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCovariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003cp\u003eMedian, years (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55.6 (32.1\u0026ndash;79.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistology\u003c/p\u003e \u003cp\u003eInvasive ductal carcinoma\u003c/p\u003e \u003cp\u003eInvasive lobular carcinoma\u003c/p\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (77)\u003c/p\u003e \u003cp\u003e4 (13)\u003c/p\u003e \u003cp\u003e3 (10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecular subtype\u003c/p\u003e \u003cp\u003eER\u0026thinsp;+\u0026thinsp;ve /Her 2 -ve\u003c/p\u003e \u003cp\u003eER\u0026thinsp;+\u0026thinsp;ve/Her 2\u0026thinsp;+\u0026thinsp;ve\u003c/p\u003e \u003cp\u003eER-ve/ Her 2\u0026thinsp;+\u0026thinsp;ve\u003c/p\u003e \u003cp\u003eER-ve/ Her 2 -ve\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (57)\u003c/p\u003e \u003cp\u003e7 (23)\u003c/p\u003e \u003cp\u003e2 (7)\u003c/p\u003e \u003cp\u003e4 (13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of initial metastatic sites\u003c/p\u003e \u003cp\u003e1 (Liver only)\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (70)\u003c/p\u003e \u003cp\u003e6 (20)\u003c/p\u003e \u003cp\u003e3 (10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from primary diagnosis to ablative radiotherapy to liver lesions\u003c/p\u003e \u003cp\u003eMedian, months (Q1 \u0026ndash; Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e371(18.5\u0026ndash;73.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of treated liver metastases\u003c/p\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(1\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of treated liver metastases (N\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003cp\u003e7\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic classification\u003c/p\u003e \u003cp\u003eInduced OM\u003c/p\u003e \u003cp\u003eRepeat OM\u003c/p\u003e \u003cp\u003eDe novo OM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (40%)\u003c/p\u003e \u003cp\u003e15 (50%)\u003c/p\u003e \u003cp\u003e3 (10%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLines of systemic therapy pre ablative radiotherapy to liver lesions\u003c/p\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (0\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial diameter of largest metastatic lesion for treatment (cm)\u003c/p\u003e \u003cp\u003eMedian (Q1 - Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.15 (2.4\u0026ndash;5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment Indication\u003c/p\u003e \u003cp\u003eOP\u003c/p\u003e \u003cp\u003eOM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (73)\u003c/p\u003e \u003cp\u003e8 (27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystemic therapy post ablative radiotherapy to liver lesions\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (93)\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBED\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003cp\u003eMedian (Q1 - Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e122.1 (97.9\u0026ndash;174.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of fractions\u003c/p\u003e \u003cp\u003eMedian (Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (5\u0026ndash;10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of fractions\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e6\u003c/p\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (50)\u003c/p\u003e \u003cp\u003e12 (40)\u003c/p\u003e \u003cp\u003e3 (10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cem\u003eAcronyms \u0026ndash; ER - Estrogen; OM - Oligometastases; OP - Oligoprogression; BED - biological equivalent dose;\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eOutcomes Post Hypo Fractionated Rt Treatment\u003c/h3\u003e\n\u003cp\u003eMedian follow-up for the entire cohort was 14.6 (range 0.9\u0026ndash;156.2) months. The LC of treated metastatic lesions at 1 and 3years was 100%. Only one local failure (patient classified as induced OMD receiving treatment for OP) was identified at 40 months post RT. This patient had ER/PR negative, HER2 positive breast cancer, they received a BED\u003csub\u003e3\u003c/sub\u003e of 93 Gy in 10 fractions and were still alive at the time of last follow up (13-years post RT).\u003c/p\u003e \u003cp\u003eMedian OS for the entire cohort was 57.7 months (Range 0.9\u0026ndash;156.2 months). One year and two-year survival was 89% and 63% respectively. Larger size, size greater than 3 cm (median Q1, Q3; 2.4, 5.1), of treated liver metastatic lesion was the only variable predictive of worse survival (HR 1.35 [95%CI: 1.04\u0026ndash;1.75] p\u0026thinsp;=\u0026thinsp;0.023) on UVA, however it was not significant on MVA (p\u0026thinsp;=\u0026thinsp;0.066). (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and Multivariable Analysis of Overall Survival\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eOverall Survival\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate Analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eMultivariable Analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecular subtype\u003c/p\u003e \u003cp\u003e(ER\u0026thinsp;+\u0026thinsp;ve /Her 2 -ve\u003c/p\u003e \u003cp\u003eOthers)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.33\u0026ndash;3.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment Intent\u003c/p\u003e \u003cp\u003eOM\u003c/p\u003e \u003cp\u003eOP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99\u0026ndash;21.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.97\u0026ndash;21.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.074\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEORTC classification\u003c/p\u003e \u003cp\u003eRepeat\u003c/p\u003e \u003cp\u003eInduced\u003c/p\u003e \u003cp\u003eDe Novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e2.04\u003c/p\u003e \u003cp\u003e2.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.56\u0026ndash;7.45\u003c/p\u003e \u003cp\u003e0.42\u0026ndash;11.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.46*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLines of systemic therapy pre ablative liver RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.93\u0026ndash;1.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.58\u0026ndash;1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize of largest metastatic liver lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.04\u0026ndash;1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.023\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.98\u0026ndash;1.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBED\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;100\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.27\u0026ndash;6.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eAcronyms \u0026ndash; ER - Estrogen; EORTC-European Organization for Research and Treatment of Cancer; OM - Oligometastases; OP - Oligoprogression; RT - Radiotherapy; BED - biological equivalent dose; HR - Hazard ratio; CI - Confidence Interval. *global p-value\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHalf of patients developed disease progression outside of the treated liver metastases, with a median time to progression post RT of 4.8 (range 0.8\u0026ndash;114.7) months. The majority were patients with induced OMD (11 patients; 73%), followed by repeat (3 patients; 20%) and de novo OMD (1 patient; 7%). Oligo-progression was the most common indication for liver RT in patients who subsequently developed further disease progression (80%). The most common sites of distant failure were lung 33% (5/15) and bone 27% (4/15). Other sites included brain, lymph nodes and omental metastases.\u003c/p\u003e \u003cp\u003eClassification of metastases and indication of treatment were the only variables significantly associated with disease progression on UVA. Patients with induced OMD had a statistically significant higher rate of progression (HR 4.77, p\u0026thinsp;=\u0026thinsp;0.01) on UVA compared to others, which trended to significance on MVA (HR 3.23, p\u0026thinsp;=\u0026thinsp;0.051). Disease progression outside of the treated liver was more likely in patients where the indication of treatment was oligo-progression (HR 3.72, p\u0026thinsp;=\u0026thinsp;0.044). (Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and Multivariable Analysis of Progression Free Survival\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eProgression Free Survival\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate Analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eMultivariable Analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecular subtype\u003c/p\u003e \u003cp\u003e(ER\u0026thinsp;+\u0026thinsp;ve /Her 2 -ve\u003c/p\u003e \u003cp\u003eOthers)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u0026ndash;2.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment Intent\u003c/p\u003e \u003cp\u003eOM\u003c/p\u003e \u003cp\u003eOP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.04\u0026ndash;13.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.044\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.67\u0026ndash;16.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEORTC classification\u003c/p\u003e \u003cp\u003eRepeat\u003c/p\u003e \u003cp\u003eInduced\u003c/p\u003e \u003cp\u003eDe Novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003cp\u003e4.77\u003c/p\u003e \u003cp\u003e3.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.44\u0026ndash;15.80\u003c/p\u003e \u003cp\u003e0.61\u0026ndash;19.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.022\u003c/b\u003e*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003cp\u003e3.23\u003c/p\u003e \u003cp\u003e6.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.95\u0026ndash;10.96\u003c/p\u003e \u003cp\u003e1\u0026ndash;45.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.051*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLines of systemic therapy pre ablative liver RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.95\u0026ndash;1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.76\u0026ndash;1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize of largest metastatic liver lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.93\u0026ndash;1.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBED\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;100\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.14\u0026ndash;1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eAcronyms \u0026ndash; ER - Estrogen; OM - Oligometastases; OP - Oligoprogression; RT - Radiotherapy; BED - biological equivalent dose; HR - Hazard ratio; CI - Confidence Interval. *global p-value\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003ePre-hypo Fractionated Rt And Post Hypo Fractionated Rt Systemic Treatment\u003c/h3\u003e\n\u003cp\u003eAll patients, but one, received some form of systemic therapy from initial diagnosis to receipt of ablative liver RT (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median lines of pre-ablative RT systemic therapy received by all patients were 2 (range 0\u0026ndash;6). Seventeen patients (56%) were switched to next line systemic therapy post liver RT, i.e. 10 patients at different points of documented disease progression and 7 in the immediate period after receipt of RT without indication of progression. The median time to second line ST after RT was 9.9 (range 1\u0026ndash;114) months. For patients initiated on second line systemic therapy at disease progression having continued pre-RT systemic therapy, the median time was 5.4 (range 2\u0026ndash;114) months in comparison with 19.1 (4.4\u0026ndash;26.4) months for patients initiated on another ST at time of RT and second line at time of disease progression. No variable on UVA was predictive of switching to second line systemic therapy post RT as per Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate Analysis of Time to Next Line Systemic Therapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eTime to Next Line Systemic Therapy\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate Analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecular subtype\u003c/p\u003e \u003cp\u003eER\u0026thinsp;+\u0026thinsp;ve /Her 2 -ve\u003c/p\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.32\u0026ndash;2.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEORTC classification\u003c/p\u003e \u003cp\u003eRepeat\u003c/p\u003e \u003cp\u003eInduced\u003c/p\u003e \u003cp\u003eDe Novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.25\u003c/p\u003e \u003cp\u003e1.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.45\u0026ndash;3.53\u003c/p\u003e \u003cp\u003e0.46\u0026ndash;3.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.88*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLines of systemic therapy pre ablative liver RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99\u0026ndash;1.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize of largest metastatic liver lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.95\u0026ndash;1.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBED\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;100\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.12\u0026ndash;1.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment intent\u003c/p\u003e \u003cp\u003eOM\u003c/p\u003e \u003cp\u003eOP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.51,3.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eAcronyms \u0026ndash; ER - Estrogen; OM - Oligometastases; OP - Oligoprogression; RT - Radiotherapy; BED - biological equivalent dose; HR - Hazard ratio; CI - Confidence Interval. *global p-value\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eAcute And Late Toxicities\u003c/h3\u003e\n\u003cp\u003eAcute grade 1 and 2 toxicities were reported in 20/30 (66%), with the most common acute toxicities of nausea (68%) and fatigue (61%) reported. One patient developed a CTCAE (version 4.0) grade 3 RT related gastric ulcer within 3 months of treatment confirmed by endoscopy after presenting with hematemesis. The patient had two liver metastases treated. One of the lesions was in segment 3 of the liver adjacent to the stomach and was prescribed 30Gy in 5 fractions. The smaller second lesion in segment 6 was prescribed 40Gy in 5 fractions. An abdominal compression system was used for motion management including image guidance for each treatment session. They received prophylactic proton pump inhibitors and anti-nausea medication for the duration of the treatment as per standard institutional practice. The maximum dose to the stomach was 31Gy and a corresponding mean of 12Gy. Gastritis was managed by medication alone with a proton pump inhibitor and the patient recovered clinically on next follow up. No late CTCAE grade 2 or higher radiotherapy related toxicities were recorded.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHypo-fractionated liver RT, regardless of metastatic classification, resulted in excellent LC of treated metastatic liver lesions: 1 and 3- year LC in our cohort was 100%. These outcomes are consistent with current literature describing patients with metastatic breast cancer treated with liver SBRT, reporting 1 and 2-year LC rates of 88\u0026ndash;100% and 75\u0026ndash;88%, respectively \u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOne and two-year overall survival rates of 89% and 63% described in this study were also similar to that reported in the literature \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. The only significant variable associated with survival was the size of the treated liver metastases (\u0026gt;\u0026thinsp;3cm), with larger sized metastases associated with worse survival. Larger metastases have previously been associated with poorer LC in patients with metastatic breast cancer receiving curative intent SBRT \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. This has been attributed to an increased risk of micro-metastatic disease\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, notable in larger sized lesions likely resulting in distant failure hence poor survival.\u003c/p\u003e \u003cp\u003eAbout half of patients described developed early disease progression, with a median PFS of 4.8 months. A difference in PFS was seen between metastatic classes. There is a paucity of clinical data describing breast cancer patient outcomes as per ESTRO/EORTC classification system; induced oligo progression has been shown to be associated with worse survival in non-breast cancer patients. \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Tan et al retrospectively described a cohort of 120 patients with metastatic breast cancer treated with SBRT to various anatomical sites (24 patients had liver SBRT), noting a difference in OS and PFS in favor of patients with OMD compared to OP disease \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. These findings suggest that differences in survival outcomes may exists based on classification of metastatic disease.\u003c/p\u003e \u003cp\u003eIn the setting of patients with induced OMD, in our study, these had a higher rate of progression compared to patients with repeat or de novo OMD. The recent phase IIR NRG BR002 trial\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e included non-classified oligo-metastatic breast cancer patients defined as patients with 4 or less extra-cranial metastatic lesions, required to have a controlled primary and had to be on standard of care ST for \u0026le;\u0026thinsp;12 months prior to enrolment. The study compared ablative therapy (93% SBRT, 7% surgery) to all lesions with ST versus ST alone, however reporting a 2-year PFS of 46.8%\u003csup\u003e5\u003c/sup\u003e with no difference in median PFS in patients who received the combination arm compared to ST alone (19.5 vs 23 months, p\u0026thinsp;=\u0026thinsp;0.92). By EORTC classification, this cohort, would be classified as having de novo metastatic disease \u0026ndash; either synchronous or metachronous setting. These findings highlight the need for trials with pre-defined subgroups to inform which cohort of breast cancer patients may benefit from ablative therapy in the setting of limited metastases and further inform sequencing with ST.\u003c/p\u003e \u003cp\u003eOligo-progression was the treatment indication for most patients described in this study (73%). This group of patients is commonly defined as having widespread metastatic disease with a limited number of metastases progressing on systemic therapy and are less well studied with unanswered questions on the right timing to initiate systemic therapy \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. The CURB study \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e a prospective randomized breast cancer study, treated patients with \u0026le;\u0026thinsp;5 progressing metastatic lesions with standard of care ST with or without SBRT. There was no difference in median PFS between patients who received SBRT (n\u0026thinsp;=\u0026thinsp;24) and those who did not (n\u0026thinsp;=\u0026thinsp;23) (18 vs 19 weeks, p\u0026thinsp;=\u0026thinsp;0.47). One reason may be that patients with OP disease are often heavily pretreated with systemic therapies and harbor radioresistant clones resulting in inferior LC post ablative RT\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Patients with OP in our study received more lines of pre-RT systemic therapy compared to patients with OMD, but this did not appear to affect LC rates. A common clinical indication for ablative RT in patients with OP disease is to delay start of next line ST, especially in the setting of limited lines of ST. Interestingly in this cohort, some patients were switched to another ST in the immediate period after RT, and had a longer interval of time to switch to second line ST post RT compared to those switched at time of progression after continuing on pre RT systemic therapy. These differences were however not analyzed further for statistical significance and warrant to be further studied in a prospective setting to inform appropriate timing of switching to next line ST when ablative RT is considered in the treatment plan.\u003c/p\u003e \u003cp\u003eBreast cancer is recognized generally as being radiosensitive, however there is limited data on the impact of molecular subtypes. With the recently updated TNM staging accounting for molecular classification, it has not yet been established if radiotherapy should be altered to account for the potential variation in biology. Evidence supporting dose escalation in the setting of K-RAS mutant colorectal\u003csup\u003e\u003cspan additionalcitationids=\"CR27 CR28 CR29\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e cancer suggests intrinsic biology matters. Neither molecular subtype or BED\u0026thinsp;\u0026gt;\u0026thinsp;100 Gy\u003csub\u003e3\u003c/sub\u003e impacted primary or secondary outcomes in this retrospective review. It is poorly understood how different molecular subtypes respond to RT\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Yard et al, described breast cancer cell lines with elevated \u003cem\u003eERBB2\u003c/em\u003e, being associated with radiation resistance prior to Her 2 targeted systemic therapy introduction\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Subsequent studies have however shown that trastuzumab, sensitizes breast cancer cells to radiation by enhancing radiation induced apoptosis conferring radiosensitivity which ultimately translates to superior LC\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. The small subset of Her 2 positive patients precluded a meaningful analysis to compare with findings from precedent studies described.\u003c/p\u003e \u003cp\u003eRadiation dose is an established predictor of local control, \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e and in this study, local control was excellent regardless of dose received. This seemingly reaffirms the radiosensitive nature of breast cancer which is increasingly being described. However, a study by Klement et al who investigated tumor control in patients with liver metastases receiving SBRT found that compared with other histology, breast cancer had the strongest relationship between LC and largest BED (using an alpha/beta 10) \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Conversely, Tan H et al ,found no association between BED (using an alpha/beta 3) or molecular subtype and local control in breast cancer patients receiving SBRT to extracranial metastases in varying anatomical locations similar to findings in this liver specific study.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDue to its retrospective nature, this study has limitations which include the presence of missing data, reporting bias, selection bias and confounders such as the use of pre- and post- ablation systemic therapy and evolving systemic treatment options during the study period. Also, due to the long period of time over which patients were treated, there have been changes to how patients are managed, such as radiological staging (CT vs MR) and systemic therapies. However, several interesting questions have been brought forward regarding the evolution of the integration of ablative RT in the setting of metastatic breast cancer. It is apparent, on literature review, there is a paucity of data describing patients with breast cancer according to the different classes of metastatic disease, indications of treatment, systemic therapies and molecular subtype \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Such variables should guide future studies with the aim to better prognosticate patients\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e who will likely benefit from ablative radiotherapy and optimum sequencing with evolving modern systemic therapies \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e, aiding clinician and patient decision making.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eHypo-fractionated ablative liver radiotherapy in patients with MBCa provides safe, tolerable treatment with excellent LC. Further studies are needed to identify patients with MBCa according to metastatic class who might benefit from ablative RT.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr Elizabeth Guimond and Tim Craig who both had no role in study design, data collection, data analysis, data interpretation, or writing of the report, but guided in clarifying technical details on treatment information.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo pertinent conflict of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received institutional approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJi L et al (2021) Risk and prognostic factors of breast cancer with liver metastases. 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Br J Radiol 86:1\u0026ndash;10\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYard BD et al of cancer to DNA damage.1\u0026ndash;14( 2016) doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/pj.2016.37\u003c/span\u003e\u003cspan address=\"10.1038/pj.2016.37\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiang K et al (2003) Sensitization of breast cancer cells to radiation by trastuzumab. Mol Cancer Ther 2:1113\u0026ndash;1120\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChappell R, Nondahl DM, Fowler JF (1995) Modeling Dose and Local Control in Radiotherapy. 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Int J Radiat Oncol. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ijrobp.2022.06.067\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2022.06.067\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePal SK et al (2012) Impact of modern chemotherapy on the survival of women presenting with de novo metastatic breast cancer.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Liver metastasis, Breast cancer, Ablative Radiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-2234222/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2234222/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGrowing data support the safe and efficacious use of ablative radiotherapy in the setting of liver metastases, with some studies suggesting that patients with metastatic breast cancer (MBCa) do better than patients with metastases from other cancers. \u0026nbsp;This study aims to retrospectively review clinical outcomes of patients with MBCa following liver radiotherapy (RT).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and Methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with MBCa who received liver hypo fractionated ablative RT between 2004 – 2020 were classified according to metastatic classification and treatment intent (i.e., oligo-metastatic (OM) or oligo-progressive (OP)). Demographics, disease characteristics and treatment characteristics were collated. Primary outcome was local control (LC) of treated metastases. Secondary outcomes included overall survival (OS), progression-free survival (PFS), and time to next line systemic therapy (ST), analyzed by univariate (UVA) and multi-variable analysis (MVA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThirty MBCa patients with 50 liver metastases treated with 5 – 10 fraction ablative intent RT were identified for analysis. Median follow-up was 14.6 months (range 0.9 - 156.2 months). Mean age was 55.6 years (range 32.1 - 79.3 years); 53% were ER+/HER2-ve and 33% HER2+ve. Class of metastatic disease was described as – induced (12 patients, 40%), repeat (15 patients, 50%) and de novo (3 patients, 10%) (1 synchronous, 2 metachronous). Indication of treatment was OP (73%) and OM (27%). Median size of treated liver metastases (LM) was 3.1 cm (range 1cm – 8.8 cm) and the median dose delivered was 40Gy (range 30Gy-60Gy).\u003c/p\u003e\n\u003cp\u003e1 and 3-year LC rates were 100%. Median OS was 57.7-months with size of treated liver metastases predictive of overall survival (HR 1.35, p=0.023) on UVA. Median time to progression post treatment was 4.8 months (0.8 – 114.7). Patients with induced OMD had a significantly higher rate of progression (HR 4.77, p=0.01) on UVA compared to others, which trended to significance on MVA (HR 3.23, p=0.051).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHypo-fractionated ablative liver RT in patients with MBCa provides safe, tolerable treatment with excellent LC. Further studies assessing the impact, ideal sequencing, and indications of RT in each metastatic class in MBCa are required.\u003c/p\u003e","manuscriptTitle":"Clinical Outcomes of Patients with Metastatic Breast Cancer treated with Hypo-Fractionated Liver Radiotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-11-07 06:32:57","doi":"10.21203/rs.3.rs-2234222/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c987b6c7-ff37-440d-a2b8-24e2f6ebc760","owner":[],"postedDate":"November 7th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-11-22T07:11:18+00:00","versionOfRecord":[],"versionCreatedAt":"2022-11-07 06:32:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2234222","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2234222","identity":"rs-2234222","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}