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      Stereotactic Body Radiotherapy (SBRT) for liver metastasis – clinical outcomes from the international multi-institutional RSSearch® Patient Registry

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          Abstract

          Background

          Stereotactic body radiotherapy (SBRT) is an emerging treatment option for liver metastases in patients unsuitable for surgery. We investigated factors associated with clinical outcomes for liver metastases treated with SBRT from a multi-center, international patient registry.

          Methods

          Patients with liver metastases treated with SBRT were identified in the RSSearch® Patient Registry. Patient, tumor and treatment characteristics associated with treatment outcomes were assessed. Dose fractionations were normalized to BED 10. Overall survival (OS) and local control (LC) were evaluated using Kaplan Meier analysis and log-rank test.

          Results

          The study included 427 patients with 568 liver metastases from 25 academic and community-based centers. Median age was 67 years (31–91 years). Colorectal adenocarcinoma (CRC) was the most common primary cancer. 73% of patients received prior chemotherapy. Median tumor volume was 40 cm 3 (1.6–877 cm 3), median SBRT dose was 45 Gy (12–60 Gy) delivered in a median of 3 fractions [ 15]. At a median follow-up of 14 months (1–91 months) the median overall survival (OS) was 22 months. Median OS was greater for patients with CRC (27 mo), breast (21 mo) and gynecological (25 mo) metastases compared to lung (10 mo), other gastro-intestinal (GI) (18 mo) and pancreatic (6 mo) primaries ( p < 0.0001). Smaller tumor volumes (< 40 cm 3) correlated with improved OS (25 months vs 15 months p = 0.0014). BED 10 ≥ 100 Gy was also associated with improved OS (27 months vs 15 months p < 0.0001). Local control (LC) was evaluable in 430 liver metastases from 324 patients. Two-year LC rates was better for BED 10 ≥ 100 Gy (77.2% vs 59.6%) and the median LC was better for tumors < 40 cm 3 (52 vs 39 months). There was no difference in LC based on histology of the primary tumor.

          Conclusions

          In a large, multi-institutional series of patients with liver metastasis treated with SBRT, reasonable LC and OS was observed. OS and LC depended on dose and tumor volume, while OS varied by primary tumor. Future prospective trials on the role of SBRT for liver metastasis from different primaries in the setting of multidisciplinary management including systemic therapy, is warranted.

          Trial registration

          Clinicaltrials.gov: NCT01885299.

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          Most cited references41

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          Actual 10-year survival after resection of colorectal liver metastases defines cure.

          Resection of colorectal liver metastases (CLM) in selected patients has evolved as the standard of care during the last 20 years. In the absence of prospective randomized clinical trials, a survival benefit has been deduced relative to historical controls based on actuarial data. There is now sufficient follow-up on a significant number of patients to address the curative intent of resecting CLM. Retrospective review of a prospectively maintained database was performed on patients who underwent resection of CLM from 1985 to 1994. Postoperative deaths were excluded. Disease-specific survival (DSS) was calculated from the time of hepatectomy using the Kaplan-Meier method. There were 612 consecutive patients identified with 10-year follow-up. Median DSS was 44 months. There were 102 actual 10-year survivors. Ninety-nine (97%) of the 102 were disease free at last follow-up. Only one patient experienced a disease-specific death after 10 years of survival. In contrast, 34% of the 5-year survivors suffered a cancer-related death. Previously identified poor prognostic factors found among the 102 actual 10-year survivors included 7% synchronous disease, 36% disease-free interval less than 12 months, 25% bilobar metastases, 50% node-positive primary, 39% more than one metastasis, and 35% tumor size more than 5 cm. Patients who survive 10 years appear to be cured of their disease, whereas approximately one third of actual 5-year survivors succumb to a cancer-related death. In well-selected patients, there is at least a one in six chance of cure after hepatectomy for CLM. The presence of poor prognostic factors does not preclude the possibility of long-term survival and cure.
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            Radiation-associated liver injury.

            The liver is a critically important organ that has numerous functions including the production of bile, metabolism of ingested nutrients, elimination of many waste products, glycogen storage, and plasma protein synthesis. The liver is often incidentally irradiated during radiation therapy (RT) for tumors in the upper- abdomen, right lower lung, distal esophagus, or during whole abdomen or whole body RT. This article describes the endpoints, time-course, and dose-volume effect of radiation on the liver. Published by Elsevier Inc.
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              Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival.

              To evaluate the long-term survival of patients resected for primarily unresectable colorectal liver metastases (CRLM) downstaged by systemic chemotherapy and to use prognostic factors of outcome for a model predictive of survival on a preoperative setting. Surgery of primarily unresectable CRLM after downstaging chemotherapy is still questioned, and prognostic factors of outcome are lacking. From a consecutive series of 1439 patients with CRLM managed in a single institution during an 11-year period (1988-1999), 1104 (77%) initially unresectable (NR) patients were treated by chemotherapy and 335 (23%) resectable were treated by primary liver resection. Chemotherapy mainly consisted of 5-fluorouracil and leucovorin combined to oxaliplatin (70%), irinotecan (7%), or both (4%) given as chronomodulated infusion (87%). NR patients were routinely reassessed every 4 courses. Surgery was reconsidered every time a documented response to chemotherapy was observed. Among 1104 NR patients, 138 "good responders" (12.5%) underwent secondary hepatic resection after an average of 10 courses of chemotherapy. At time of diagnosis, mean number of metastases was 4.4 (1-14) and mean maximum size was 5.2 cm (1-25). Extrahepatic tumor was present in 52 patients (38%). Multinodularity or extrahepatic tumor was the main cause of initial unresectability. All factors likely to be predictive of survival after liver resection were evaluated by uni- and multivariate analysis. Estimation of survival was adjusted on risk factors available preoperatively. Seventy-five percent of procedures were major hepatectomies (> or =3 segments) and 93% were potentially curative. Liver surgery was combined to portal embolization, to ablative treatment, or to a second-stage hepatectomy in 42 patients (30%) and to resection of extrahepatic tumor in 41 patients (30%). Operative mortality within 2 months was 0.7%, and postoperative morbidity was 28%. After a mean follow-up of 48.7 months, 111 of the 138 patients (80%) developed tumor recurrence, 40 of which were hepatic (29%), 12 extrahepatic (9%), and 59 both hepatic and extrahepatic (43%). Recurrence was treated in 52 patients by repeat hepatectomy (71 procedures) and in 42 patients by extrahepatic resection (77 procedures). Survival was 33% and 23% at 5 and 10 years with a disease-free survival of 22% and 17%, respectively. It was decreased as compared with that of patients primarily resected within the same period (48% and 30% respectively, P = 0.01). At the last follow-up, 99 patients had died (72%) and 39 (28%) were alive; 25 were disease free (18%) and 14 had recurrence (10%). At multivariate analysis, 4 preoperative factors were independently associated to decreased survival: rectal primary, > or =3 metastases, maximum tumor size >10 cm, and CA 19-9 >100 UI/L. Mean adjusted 5-year survival according to the presence of 0, 1, 2, 3, or 4 factors was 59%, 30%, 7%, 0%, and 0%. Modern chemotherapy allows 12.5% of patients with unresectable CRLM to be rescued by liver surgery. Despite a high rate of recurrence, 5-year survival is 33% overall, with a wide use of repeat hepatectomies and extrahepatic resections. Four preoperative risk factors could select the patients most likely to benefit from this strategy.
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                Author and article information

                Contributors
                + 1 570 2143420 , amahadevan@geisinger.edu
                blanck@saphir-rc.com
                rlancmd@gmail.com
                anujpeddada@centura.org
                SSundararaman@mhs.net
                DDAmbrosio@barnabashealth.org
                sharmalahr@comcast.net
                David.James.Perry@medstar.net
                James.Kolker@uphs.upenn.edu
                jdavis@therss.org
                Journal
                Radiat Oncol
                Radiat Oncol
                Radiation Oncology (London, England)
                BioMed Central (London )
                1748-717X
                13 February 2018
                13 February 2018
                2018
                : 13
                : 26
                Affiliations
                [1 ]ISNI 0000 0004 0394 1447, GRID grid.280776.c, Geisinger Health System, ; 100 N Academy Ave, Danville, PA 17822 USA
                [2 ]ISNI 0000 0004 0646 2097, GRID grid.412468.d, Department of Radiation Oncology, , University Medical Center Schleswig-Holstein, ; Kiel, Germany
                [3 ]Saphir Radiosurgery Center Guestrow, Frankfurt, Germany
                [4 ]Department of Radiation Oncology, Crozer Keystone Health Care Center, Philadelphia CyberKnife, Havertown, PA USA
                [5 ]Department of Radiation Oncology, Centura Health, Colorado Springs, CO USA
                [6 ]ISNI 0000 0004 0411 5227, GRID grid.415312.0, Department of Radiation Oncology, , Memorial Regional Hospital, ; Hollywood, FL USA
                [7 ]ISNI 0000 0004 0448 5762, GRID grid.414657.5, Department of Radiation Oncology, , New Jersey CyberKnife at Community Medical Center, ; Toms River, NJ USA
                [8 ]Department of Radiation Oncology, St. Mary’s Medical Center, Huntington, WV USA
                [9 ]ISNI 0000 0000 9148 7539, GRID grid.415030.3, Department of Radiation Oncology, , Medstar Franklin Square Medical Center, ; Baltimore, MD USA
                [10 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Radiation Oncology, , University of Pennsylvania, ; Philadelphia, PA USA
                [11 ]The Radiosurgery Society, San Mateo, CA USA
                Author information
                http://orcid.org/0000-0003-3555-4217
                Article
                969
                10.1186/s13014-018-0969-2
                5811977
                29439707
                a08e3220-4925-4f4b-9628-9d3df4f2a87d
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 28 November 2017
                : 2 February 2018
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                sbrt,liver metastasis,rssearch registry
                Oncology & Radiotherapy
                sbrt, liver metastasis, rssearch registry

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