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      Quality assurance analysis of hippocampal avoidance in a melanoma whole brain radiotherapy randomized trial shows good compliance

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          Abstract

          Background

          Melanoma brain metastases (MBM) often cause morbidity and mortality for stage IV melanoma patients. An ongoing randomised phase III trial (NCT01503827 – WBRT-Mel) evaluates the role of adjuvant whole brain radiotherapy (WBRT) following local treatment of MBM. Hippocampal avoidance during WBRT (HA-WBRT) has shown memory and neurocognitive function (NCF) preservation in the RTOG-0933 phase II study. This study assessed the quality assurance of HA-WBRT within the WBRT-Mel trial according to RTOG-0933 study criteria.

          Methods

          Hippocampal avoidance was allowed in approved centres with intensity-modulated radiotherapy capability. Patients treated by HA-WBRT were not randomized within the WBRT arm. The RTOG 0933 contouring Atlas was used to contour hippocampi. In the trial co-ordinating centre, patients were treated with volumetric modulated arc therapy using complementary arcs; similar techniques were used at other sites. Dosimetric data were extracted retrospectively and analysed in accordance with RTOG 0933 study constraints criteria.

          Results

          Among the 215 patients accrued to the WBRT-Mel study between April 2009 and September 2017, 107 were randomized to the WBRT arm, 22 were treated by HA-WBRT in 4 centers. Eighteen patients were treated in the same centre. The median age was 65 years. The commonest (91%) HA-WBRT schema was 30 Gy in 10 fractions. Prior to HA-WBRT, 10 patients had been treated by surgery alone, six by radiosurgery alone, four by surgery and radiosurgery and two exclusively by simultaneous integrated boost concurrent to HA-WBRT. Twenty patients were treated with intention to spare both hippocampi and two patients had MBM close to one hippocampus and were treated with intention to spare the contralateral hippocampus. According to RTOG-0933 study criteria, 18 patients (82%) were treated within constraints and four patients (18%) had unacceptable deviation in just one hippocampus.

          Conclusions

          This dosimetric quality assurance study shows good compliance (82%) according to RTOG-0933 study dosimetric constraints. Indeed, all patients respected RTOG hippocampal avoidance constraints on at least one hippocampus. In the futureanalysis of the WBRT-Mel trial, the NCF of patients on the observation arm, WBRT arm and with HA-WBRT arm will be compared.

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          Most cited references32

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          Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System.

          Population-based estimates of the incidence of brain metastases are not generally available. The purpose of this study was to calculate population-based incidence proportions (IPs) of brain metastases from single primary lung, melanoma, breast, renal, or colorectal cancer. Patients diagnosed with single primary lung, melanoma, breast, renal, or colorectal cancer (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System (MDCSS) were used for analysis. IP of brain metastases by primary site and variable of interest (race, sex, age at diagnosis of primary cancer, and Surveillance, Epidemiology, and End Results [SEER] stage of primary cancer) was calculated with 95% CIs. Total IP percentage (IP%) of brain metastases was 9.6% for all primary sites combined, and highest for lung (19.9%), followed by melanoma (6.9%), renal (6.5%), breast (5.1%), and colorectal (1.8%) cancers. Racial differences were seen with African Americans demonstrating higher IP% of brain metastases compared with other racial groups for most primary sites. IP% was significantly higher for female patients with lung cancer, and significantly higher for male patients with melanoma. The highest IP% of brain metastases occurred at different ages at diagnoses: age 40 to 49 years for primary lung cancer; age 50 to 59 years for primary melanoma, renal, or colorectal cancers; and age 20 to 39 for primary breast cancer. IP% significantly increased as SEER stage of primary cancer advanced for all primary sites. Total IP% of brain metastases was lower than previously reported, and it varied by primary site, race, sex, age at diagnosis of primary cancer, and SEER stage of primary cancer.
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            Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial.

            Hippocampal neural stem-cell injury during whole-brain radiotherapy (WBRT) may play a role in memory decline. Intensity-modulated radiotherapy can be used to avoid conformally the hippocampal neural stem-cell compartment during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with prespecified comparison with a historical control of patients treated with WBRT without hippocampal avoidance. Eligible adult patients with brain metastases received HA-WBRT to 30 Gy in 10 fractions. Standardized cognitive function and quality-of-life (QOL) assessments were performed at baseline and 2, 4, and 6 months. The primary end point was the Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) at 4 months. The historical control demonstrated a 30% mean relative decline in HVLT-R DR from baseline to 4 months. To detect a mean relative decline ≤ 15% in HVLT-R DR after HA-WBRT, 51 analyzable patients were required to ensure 80% statistical power with α = 0.05. Of 113 patients accrued from March 2011 through November 2012, 42 patients were analyzable at 4 months. Mean relative decline in HVLT-R DR from baseline to 4 months was 7.0% (95% CI, -4.7% to 18.7%), significantly lower in comparison with the historical control (P < .001). No decline in QOL scores was observed. Two grade 3 toxicities and no grade 4 to 5 toxicities were reported. Median survival was 6.8 months. Conformal avoidance of the hippocampus during WBRT is associated with preservation of memory and QOL as compared with historical series. © 2014 by American Society of Clinical Oncology.
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              The biology of brain metastases-translation to new therapies.

              Brain metastases are a serious obstacle in the treatment of patients with solid tumors and contribute to the morbidity and mortality of these cancers. It is speculated that the frequency of brain metastasis is increasing for several reasons, including improved systemic therapy and survival, and detection of metastases in asymptomatic patients. The lack of preclinical models that recapitulate the clinical setting and the exclusion of patients with brain metastases from most clinical trials have slowed progress. Molecular factors contributing to brain metastases are being elucidated, such as genes involved in cell adhesion, extravasation, metabolism, and cellular signaling. Furthermore, the role of the unique brain microenvironment is beginning to be explored. Although the presence and function of the blood-brain barrier in metastatic tumors is still poorly understood, it is likely that some tumor cells are protected from therapeutics by the blood-tumor barrier, creating a sanctuary site. This Review discusses what is known about the biology of brain metastases, what preclinical models are available to study the disease, and which novel therapeutic strategies are being studied in patients.
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                Author and article information

                Contributors
                Gerald.fogarty@cancer.com.au
                Journal
                Radiat Oncol
                Radiat Oncol
                Radiation Oncology (London, England)
                BioMed Central (London )
                1748-717X
                20 July 2018
                20 July 2018
                2018
                : 13
                : 132
                Affiliations
                [1 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Melanoma Institute Australia, The University of Sydney, ; NSW North Sydney, Australia
                [2 ]ISNI 0000 0001 0131 6312, GRID grid.452351.4, Centre Oscar-Lambret, ; Lille, France
                [3 ]Mater Hospital, NSW North Sydney, Australia
                [4 ]GenesisCare, Radiation Oncology, Mater Hospital, NSW North Sydney, Australia
                [5 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Central Clinical School, , The University of Sydney, ; Camperdown, NSW Australia
                [6 ]ISNI 0000 0000 8831 109X, GRID grid.266842.c, School of Medicine and Public Health, University of Newcastle, ; NSW Callaghan, Australia
                [7 ]GenesisCare, Radiation Oncology, NSW Newcastle, Australia
                [8 ]Northern Territory Radiation Oncology, Alan Walker Cancer Care Centre, NT Darwin, Australia
                [9 ]ISNI 0000 0004 0367 1221, GRID grid.416075.1, Royal Adelaide Hospital, ; Adelaide, South Australia Australia
                [10 ]ISNI 0000 0004 1936 7304, GRID grid.1010.0, University of Adelaide, ; South Australia Adelaide, Australia
                [11 ]Australia and New Zealand Melanoma Trials Group, NSW North Sydney, Australia
                Article
                1077
                10.1186/s13014-018-1077-z
                6053726
                30029684
                f9102da0-2998-49c0-8bf2-9dabfe4a1b73
                © 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
                : 26 April 2018
                : 11 July 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001111, Cancer Australia;
                Award ID: 1084046
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                radiotherapy,whole brain radiotherapy,trial,quality assurance,intensity-modulated radiotherapy,hippocampal avoidance

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