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Hippocampal Sparing During Craniospinal Irradiation: What Did We Learn About the Incidence of Perihippocampus Metastases?
Accepted Manuscript Hippocampal sparing during Craniospinal irradiation, what did we learn about the incidence of peri hippocampus metastases? Laetitia Padovani, Frédérique Chapon, Nicolas André, Mohamed Boucekine, Anne Geoffray, Franck Bourdeau, Julien Masliah-Planchon, Line Claude, Aymeri Huchet, Anne Laprie, Stephane Supiot Bernard Coche-Dequéant, Christine Kerr, Claire Alapetite, Julie Leseur, Tandat Nguyen, Sophie Chapet, Valerie Bernier, PierreYves Bondiau, Georges Noel, Jean Louis Habrand, Stephanie Bolle, François Doz, Christelle Dufour, Xavier Muracciole, Christian Carrie PII:
S0360-3016(17)34486-3
DOI:
10.1016/j.ijrobp.2017.12.265
Reference:
ROB 24667
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 1 September 2017 Revised Date:
8 November 2017
Accepted Date: 11 December 2017
Please cite this article as: Padovani L, Chapon F, André N, Boucekine M, Geoffray A, Bourdeau F, Masliah-Planchon J, Claude L, Huchet A, Laprie A, Bernard Coche-Dequéant SS, Kerr C, Alapetite C, Leseur J, Nguyen T, Chapet S, Bernier V, Bondiau P-Y, Noel G, Habrand JL, Bolle S, Doz F, Dufour C, Muracciole X, Carrie C, Hippocampal sparing during Craniospinal irradiation, what did we learn about the incidence of peri hippocampus metastases?, International Journal of Radiation Oncology • Biology • Physics (2018), doi: 10.1016/j.ijrobp.2017.12.265. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Hippocampal sparing during Craniospinal irradiation, what did we learn about the incidence of peri hippocampus metastases?
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Laetitia Padovani, Frédérique Chapon, Nicolas André, Mohamed Boucekine, Anne Geoffray, Franck Bourdeau, Julien Masliah-Planchon, Line Claude, Aymeri Huchet, Anne Laprie, Stephane Supiot Bernard Coche-Dequéant, Christine Kerr, Claire Alapetite, Julie Leseur, Tandat Nguyen, Sophie Chapet, Valerie Bernier, Pierre-Yves Bondiau, Georges Noel, Jean Louis Habrand, Stephanie Bolle, François Doz, Christelle Dufour, Xavier Muracciole and Christian Carrie.
APHM Marseille, France (L.P., N.A., X.M.) Faculte Aix –Marseille II ( M.B) Institut Saint Joseph
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Marseille, France (F.C.) CHU Lenval Nice, France (A.G.) (L.C., C.C.) CHU Bordeaux, France (A.H.) IUCT Oncopole Toulouse, France (A.L.) Centre René Gauduchet Nantes, France (S.S) Centre Oscar Lambret
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Lille, France (B.C.-D.) ICM Montpellier, France (C.K.) Institut Curie Paris, France (F.B, C.A., F.D.) PSL Research University, Curie Institute, SiREDO pediatric cancer center & Curie Institute SIRIC, France ( F.B, J.M.P) Centre Eugène Marquis Rennes, France (J.L.) Institut Jean-Godinot Reims, France (T.N) CHU Tours France (S.C.) Centre Alexis Vautrin, France (V.B.) Centre Antoine Lacassagne, (P.Y.B.)Centre Paul Strauss Strasbourg, France (G.N.) Centre Antoine Baclesse Caen, France (J.L.H)
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Institut Gustave Roussy, France (S.B., C.D.) Universite Paris Descartes (F.D)
Corresponding author: laetitia padovani [email protected]
tel +33491384337
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fax +33491385692
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264 Bd jean Moulin 13385 Marseille cedex 5
Responsible for statistical analysis : Mohamed.boucekine [email protected]
264 Bd jean Moulin 13385 Marseille cedex 5 tel +33491384337
Running title: hippocampal metastases in medulloblastoma? Conflict of Interest: no conflict Acknowledgments: The authors thank Victoria Grace for the English writing assistance
ACCEPTED MANUSCRIPT Hippocampal sparing during Craniospinal irradiation, what did we learn about the incidence of peri hippocampus metastases?
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Running title: Hippocampal sparing for high-risk medulloblastoma ?
Summary
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Whole brain irradiation (WBI) plays a role in neurocognitive effects.
New technologies make WBI possible while sparing the hippocampal region (HA-WBI).
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As already done in adult population with primary carcinoma, to safety propose HA-WBI, our study aimed to assess the distribution of brain metastases within the peri hippocampal area (PHA) in high-risk medulloblastoma children.
In conclusion, we recommend to evaluate HA-WBI strategy for subgroup of high risk patients
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without metastatic disease
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ACCEPTED MANUSCRIPT Abstract Background Medulloblastoma represents 20% of pediatric brain tumors. For high-risk medulloblastoma (HRM) patients, the 3- to 5-year event-free survival rate has recently improved from 50% to
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more than 76%. Many survivors, however, experience neurocognitive side effects. Several retrospective studies in patients receiving whole brain irradiation (WBI) suggest a relationship between the radiation dose to the hippocampus and neurocognitive decline. The hippocampal
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avoidance-WBI (HA-WBI) approach could partially reduce neurocognitive impairment in children treated for HRM. We aimed to identify the incidence of patients with peri-
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hippocampal metastases (PHM) to assess the risk of brain relapse when sparing the hippocampal area. Methods
Between 2008 and 2011, 51 patients with HRM were treated according to the French trial
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PNET HR+5. Hippocampal contouring was manually generated in three-dimensional magnetic resonance imaging according to the RTOG 0933 atlas. The distribution of metastases was assessed relative to the hippocampus: 0 to 5 mm for the first perihippocampal
Results
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area (FPHA) and 5 to 15 mm for the rest of perihippocampal area (RPHA)
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The median age of patients was 8.79 years, with 33% being female. After a follow-up of 2.4 years, 43 patients were alive. 28 had brain metastasis at diagnosis and 2 at relapse time with 16% in FPHA and 43% in RPHA. Among 18 patients without brain metastases at diagnosis including M1 patients, none developed secondary lesions within FPHA or RPHA, after receiving 36 Gy No clinical or biological factor was significantly associated with the PHM. Conclusions
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ACCEPTED MANUSCRIPT Our results suggest to evaluate HA-WBI strategy for subgroup of high risk patients without metastatic disease Keywords High-risk medulloblastoma, hippocampal avoidance whole brain radiotherapy, neurocognitive
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effects
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ACCEPTED MANUSCRIPT Introduction Medulloblastoma (MB) accounts for 20% of brain tumors in children and adolescents under the age of 18 years. Approximately one-third of children present with metastases at diagnosis (1). Patients older than 3 years of age with disseminated MB, MB with a residual
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tumor size exceeding 1.5 cm2, or the anaplastic subtype or MB with MYC amplification are considered as high risk (2) In this subgroup of high-risk patients, the three- to five-year event-free survival rate was less than 50% until several years ago, but it has recently
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improved (76%) with the different treatment strategies now available such as high-dose
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chemotherapy (3),hyperfractionated accelerated radiotherapy, use of radiosensitizers and concurrent radiochemotherapy (4)(5)(6).
Many survivors, however, experience neurocognitive side effects such as deterioration in
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attention and executive function, poor working memory, and processing speed dysfunctions. The combination of tumor volume, tumor location, and treatment modalities is responsible for this neurocognitive impact (7)(8). Among the different treatments, whole brain radiotherapy
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plays a significant role in the deterioration of neurocognitive functions (9)(10)(11)(12).
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Preclinical and clinical data confirm that radio-induced neurocognitive toxicity is related to damage to the neural progenitor cells in the subventricular zone and hippocampus (13)(14) as well as vascular injury and glial precursor ablation. Moreover, in a rat model, whole brain radiotherapy led to a reduction in hippocampal volume, the suppression of subventricular zone neurogenesis, the loss of oligodendrocyte precursors (14)(15), and cognitive deficits (16)(15)(17). In addition, several retrospective clinical studies in adult and child populations suggest an association between the radiation dose delivered to the hippocampus and temporal
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ACCEPTED MANUSCRIPT lobes and neurocognitive decline in children treated with whole brain radiotherapy (18)(19)(20).
Modern radiotherapy techniques such as intensity-modulated radiotherapy (IMRT) make
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whole brain irradiation (WBI) possible while sparing the hippocampal region (hippocampalavoiding whole brain irradiation, HA-WBI). This reduced dose to the hippocampal region during WBI could mitigate or prevent neurocognitive impairment. In an adult phase II study
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of the Radiation Therapy Oncology Group (RTOG 0933) involving 113 patients with brain metastases from different primary carcinoma, receiving HA-WBI to 30 Gy in 10 fractions
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Gondi et al. reported a significant decrease in neurocognitive decline compared with historical control and a low incidence (4.5%) of metastases in the avoidance region of HA-WBI among patients with cerebral progression (21).
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The HA-WBI approach has the potential to partially reduce neurocognitive impairment in children with high-risk MB treated with a high-dose of craniospinal radiation provided that there is no increased risk of brain relapse in this region. To date, no study has clearly assessed
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the distribution of brain metastases in the hippocampal region in a high-risk population of children with MB, whether at the time of diagnosis or during progression.
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For this reason, our study aimed to establish retrospectively the incidence of patients with metastases in the hippocampal area before and after craniospinal irradiation in a national cohort of high-risk MB children treated according to the French primitive neuroectodermal tumor (PNET) HR+5 trial. Moreover, we investigated the relationship between clinical parameters and molecular subtypes of MB as well as the risk of peri-hippocampal disease relapse.
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ACCEPTED MANUSCRIPT Materials and Methods Treatment: Between 2009 and 2012, 51 patients aged between 5 and 18 years old with newly diagnosed high-risk medulloblastoma were treated according to the French trial PNET HR+5 protocol:
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Children received as postoperative induction chemotherapy two cycles of etoposide (500mg /m²) - carboplatin (800mg/m²), followed by two courses of thiotepa (600mg/m² per course) with autologous stem cell rescue. Risk-adapted conventional radiotherapy (RT) was delivered
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around day 45 after second transplantation. Craniospinal RT dose was 36 Gy for patients with metastatic disease or with unfavourable histology (anaplastic MB, large cell MB, MB
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with myc amplification) followed by a tumor bed boost of 18 Gy. For localized MB with postoperative residual tumor, RT was consisted of 23.4 Gy on the craniospinal axis and 54 Gy on the primitive tumor. Maintenance treatment with 6 cycles of temozolomide was planned to start between 1-3 months after the end of RT. Pathology samples were centrally reviewed at
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diagnosis according to 2007 WHO classification (Louis, 2007). Subgroup affiliation was established using nanostring targeted gene-expression profiling from paraffin-embedded or frozen samples. Disease status was assessed by MRI of head and spine. If tumor cells were
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identified in the CSF at diagnosis, CSF analysis was also performed until normalization. Tumor response was assessed by independent central review and by investigator using MRI
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and CSF analysis taken at diagnosis, after surgery, before HDCT, after the second HDCT, after RT, every 3 cycles of temozolomide and at the end of treatment. Informed consent was received from parents and/or patients. Approval from Ethics committees was available. The study was registered at the Us National Cancer Institute.
Metastasis distribution:
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ACCEPTED MANUSCRIPT Imaging were investigated during follow up and reviewed again at time of retrospective delineation. Retrospectively, all pre- and post-treatment MRI scans for patients were used to delineate the individual nodular metastases in the perihippocampal area and hippocampus.
RTOG 0933 atlas (22) by a single radiologist physician.
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Hippocampal contouring was manually generated in three-dimensional MRI according to the
(http://www.rtog.org/CoreLab/ContouringAtlases/HippocampalSparing.aspx.
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Contouring was performed on the axial and coronal gadolinium contrast-enhanced T1-
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weighted sequence and, axial T2-weighted and axial and coronal T2 flair images, from anterior to posterior, that is, from the hippocampal head to the tail,. (figure 1) The volume, location, and closest distance of each metastasis to the hippocampus were recorded. Delineation and measurements were performed in radiological department using Review station General Electric advantage windows 4.6. with Advanced software Volume viewer.
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Multimodality contouring..
The distribution of the metastases was assessed relative to the hippocampus: in the
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hippocampus and between 0 and 5 mm, 5 and 10 mm, and 10 and 15 mm from the hippocampus. We define the first part of the hippocampal area between 0 and 10 mm as the
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“first hippocampal area” and the second part from 10 to 15 mm as “the rest of the hippocampal area.” The hippocampal avoidance zones were generated by expanding the hippocampal outlines with margins of 5, 10, and 15 mm volumetrically.
Statistics: Categorical variables are presented as numbers and percentages. The significance of group differences was determined using the chi-square test and Fisher’s exact test, as appropriate. A two-sided p-value >0.05 was considered to indicate statistical significance between patients 7
ACCEPTED MANUSCRIPT with and without hippocampal area lesions according sex, age, type of surgery, histological diagnosis, spinal fluid involvement, biological subgroup, and p53 tumor status.
Results
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51 patients for high-risk MB. The median age was 8.79 years, and 17 were male (33%). Patient characteristics are described in Table 1. Because of deviations, all patients received finally 36 Gy on CSI except 5 patients who received 30.6 Gy whom 3 patients with brain
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metastasis at diagnosis
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Among the 51 patients, except for 3 patients, all diagnosis and follow up MRI including MRI imaging at relapse were available.. 33 patients presented metastases (MRI was available only for 30 in this study): 28 at diagnosis and 2 at the time of progression. Among these 30 patients, 13 children (43%) developed 21 metastases in the perihippocampal area (from
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hippocampus to 15 mm), including 5 patients (16 %) in the first hippocampal area with 2 metastases in the hippocampus and 6 metastases less than 5 mm from it. Among these 5
metastases.
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patients, 3 had more than 10 metastases, 1 had between 5 and 10 metastases, and 1 had only 2
Among the patients with M1 disease at diagnosis, only one had a metastatic relapse; in the
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pituitary area. Only one patient developed a single hippocampal lesion at relapse while he had M3 disease at diagnosis (not shown in the table). No patient with M2 disease at diagnosis developed new brain metastases in perihippocampal area. One of them developed new brain metastasis at relapse: all in posterior fossa while he had only posterior fossa disease at diagnosis. Among the 12 patients without metastatic disease at diagnosis 1 had a metastatic relapse considered outside of the total hippocampal area, with nodules along the lateral ventricles area
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ACCEPTED MANUSCRIPT The spatial distribution of metastatic brain lesions is shown in Table 2.
No clinical factor was found to be significantly associated with perihippocampal metastasis
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distribution.
Discussion
This study is the first to determine the risk of developing perihippocampal metastases to
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assess the potential interest of using HA-WBI for high-risk MB. In this study, among 30 available patients with metastases, 5 children (16%) had metastases in the first hippocampal
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area and 43% in the total hippocampal area. Only one patient (with spinal cord nodules at diagnosis) developed a single hippocampal lesion at relapse. No clinical factor was correlated with the risk of perihippocampal metastases.
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The 16% incidence rate of brain metastases at diagnosis within the perihippocampal region (hippocampus = 5 mm) in our study was very high in comparison with the rate of 4.5% in
(25).
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non-small-cell lung cancer (21), 5% in small-cell lung cancer (24), and 4.1% in breast cancer
In this context, Gondi et al. reported a significant improvement in the memory of patients
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treated with HA-WBI, with only 4.5% of patients (3 out of 67) relapsing in the hippocampal avoidance area (21). In contrast to adult patients treated with whole brain radiotherapy for metastatic disease, the medulloblastoma treatment includes craniospinal radiotherapy plus tumor bed boost irradiation. Although it has not been proven in a randomized trial, pediatric radiation oncologists are now moving away from posterior fossa to tumor bed volume with the aim to reduce the boost volume (26)(27) and decrease the dose delivered to the temporal lobes and hippocampus (7)(28). However, the impact of tumor bed boost on the hippocampus
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ACCEPTED MANUSCRIPT is not negligible (18)(29). Brodin et al. reported the results of a dosimetric study in 17 pediatric patients with MB to assess the impact of tumor boost dose on the mean hippocampal dose according to the clinical tumor volume (CTV = tumor bed plus margins of 5, 10, and 15 mm, or posterior fossa) and radiotherapy technique: three-dimensional conformal
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radiotherapy, IMRT, and proton therapy (29). They reported statistically significant correlations between the size of the planned target volume (PTV = CTV plus 5 mm) and the mean hippocampal dose. They also showed that IMRT can add 6.9, 9.5, and 11.8 Gy to the
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hippocampal dose according to margins of 5, 10, and 15 mm around the tumor bed, respectively. Proton therapy would be able to limit this hippocampal boost dose to 3.3, 6.1,
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and 8.7 Gy using the same respective margins.
Different studies have analyzed the quality of PTV coverage in HA-WBI and the level of the decreased dose delivered to the hippocampal region. Gondi et al. reported the PTV coverage
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and hippocampus dose in five patients treated with HA-WBI delivered at 30 Gy in 10 fractions. With an hippocampal avoidance area as hippocampus volume plus 5 mm, the mean dose (normalized to 2 Gy fractions) received by the hippocampus ranged between 4.9 and 7.3
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Gy, with a maximum dose between 12.8 and 15.3 Gy for a PTV coverage between 93 and 95% (22). For the craniospinal part of medulloblastoma irradiation, HA-WBI decreases the
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hippocampal dose by around 15% using IMRT, while the brain coverage was relaxed from 98 to 95% (29).
In a dosimetric feasibility study of hippocampal sparing in patients treated for MB, Blomstrand et al. estimated that the frequency of adverse neurological effects could be dramatically reduced (30) Brodin et al. also investigated hippocampal sparing with IMRT during focal boost radiotherapy, which induces a considerable estimated clinical benefit using a dose-response model (29).
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One of the major questions related to this study remains unanswered: what is the dose threshold below which hippocampal stem cell neurogenesis is preserved and which dose is clinically relevant for the pediatric patient in terms of decreased neurocognitive side effects?
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Merchant et al. reported that increasing mean doses to hippocampi had a significant negative impact on estimated intellectual quotient, reading, and spelling in children, with a younger age at the time of irradiation amplifying this impact (6). Yet, no threshold in terms of dose or
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volume could be identified as a target for the HA-WBI approach. Several studies have reported different threshold founded correlated with neurocognitive improvement such as less
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than 7.3 Gy to 40% of bilateral hippocampi (31), maximal dose of 9 Gy to 100% of hippocampi (20) or maximal dose of 5.83 to 100% of the bilateral hippocampal in an adult study (32)
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Regarding our limited knowledge, it seems that for medulloblastoma, the maximal dose to hippocampus should be at least less than 5Gy for craniospinal treatment while taking into account the additional tumor boost dose estimated at around 9 Gy using IMRT (29). For this
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reason, we advocate defining the perihippocampal area as the hippocampus plus 10 to 15 mm
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to be able to correctly decrease the total hippocampal dose.
In our study, the 16% incidence rate of hippocampal metastases in the first area and 43% from the hippocampus to 15 mm should be considered as high rates. Based on the results of the quality control of radiotherapy in MB, which significantly reduced the incidence of frontal recurrence (33), the risk of recurrence in these perihippocampal regions with a high gradient dose resulting from HA-WBI could increase substantially. Our study results do not encourage
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ACCEPTED MANUSCRIPT the use of craniospinal irradiation with hippocampal sparing for children with metastatic medulloblastoma. However, among 18 available patients without brain metastases at diagnosis including M1 patients, only 2 developed brain metastases and out of hippocampi area, after receiving 36 Gy.
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These results indicate that hippocampi sparing technique for craniospinal irradiation in high risk no metastatic medulloblastoma patients could be prospectively investigated
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The size of population could not allow us to identify molecular groups that were significantly associated with a very low risk of perihippocampal metastases. However, in 2013,
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Ramaswamy et al. reported very rarely distant metastasis in atients in the SHH group while group 3 and 4 patients developed a recurrence of brain metastases independently of treatment effect (33). In our series, seven patients were classified in the SHH group, including three patients with positive p53 status. Two presented multiple brain metastases at diagnosis, all
patients.
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with perihippocampal lesions. No brain or spinal metastasis was observed for p53-negative
Indeed, a sample of high-risk MB patients treated without radiotherapy could be an interesting
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population to study in order to assess the real risk of perihippocampal relapse. This discussion could also be extended to average-risk medulloblastoma patients and low risk
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medulloblastoma where focusing on hippocampal avoidance could be an interesting alternative to global decrease in doses. Other therapeutic strategies attempt to decrease the neurocognitive impairment of radiotherapy with some promising results yet to be confirmed, such as hyperfractionated radiotherapy (34)(35), protontherapy (36), and pharmacological interventions. (8)
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ACCEPTED MANUSCRIPT If the overall incidence of patients with brain metastases in the hippocampal area before craniospinal irradiation in the metastatic medulloblastoma subgroup is elevated, and does not support hippocampi sparing at this time. In opposite, the lack of hippocampi area relapse among high risk patients without metastatic disease in our study suggest that this group may
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benefit from hippoacmapi sparing prospective investigation . This national French sample, however, needs to be increased in order to confirm the subgroups of patients available for
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HA-WBI.
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31. Gondi V, Hermann BP, Mehta MP, Tomé WA. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):e487–93.
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32. Tsai P-F, Yang C-C, Chuang C-C, Huang T-Y, Wu Y-M, Pai P-C, et al. Hippocampal dosimetry correlates with the change in neurocognitive function after hippocampal sparing during whole brain radiotherapy: a prospective study. Radiat Oncol Lond Engl. 2015 Dec 10;10:253. 33. Carrie C, Hoffstetter S, Gomez F, Moncho V, Doz F, Alapetite C, et al. Impact of targeting deviations on outcome in medulloblastoma: study of the French Society of Pediatric Oncology (SFOP). Int J Radiat Oncol Biol Phys. 1999 Sep 1;45(2):435–9.
34. Carrie C, Grill J, Figarella-Branger D, Bernier V, Padovani L, Habrand JL, et al. Online quality control, hyperfractionated radiotherapy alone and reduced boost volume for standard risk medulloblastoma: long-term results of MSFOP 98. J Clin Oncol Off J Am Soc Clin Oncol. 2009 Apr 10;27(11):1879–83.
35.
Câmara-Costa H, Resch A, Kieffer V, Lalande C, Poggi G, Kennedy C, et al. 17
ACCEPTED MANUSCRIPT Neuropsychological Outcome of Children Treated for Standard Risk Medulloblastoma in the PNET4 European Randomized Controlled Trial of Hyperfractionated Versus Standard Radiation Therapy and Maintenance Chemotherapy. Int J Radiat Oncol Biol Phys. 2015 Aug 1;92(5):978–85.
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36. Kahalley LS, Ris MD, Grosshans DR, Okcu MF, Paulino AC, Chintagumpala M, et al. Comparing Intelligence Quotient Change After Treatment With Proton Versus Photon Radiation Therapy for Pediatric Brain Tumors. J Clin Oncol Off J Am Soc Clin Oncol. 2016 Apr 1;34(10):1043–9.
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ACCEPTED MANUSCRIPT Table 1: Patient characteristics Caracteristics
Number of patients (%)
Sex 17
Male Ventriculoperitoneal shunt Ventriculoventricular shunt External shunt Extent of resection, including second surgery Total Partial Biopsy
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28 9 10 4
Biological group WNT SHH p53-/SHH p53+ 3 4 Undetermined
3 4/3 15 15 11
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Isolated M1 Non-isolated M1
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Initial presentation and relapse time M2 M3 M2/M3
47 3 1
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Histologic subtype CMB DMB LC/A MB Unclassifiable
M0 patients
34 6 22 4
12 6 8 30 16 9 5
Unavailable MRI
3
M1non isolated
1
M3
1
Unknown
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Female
1
Survival Alive
43
Dead
8
Abbreviations: M1, presence of tumor cells in the CSF at diagnosis; M2, metastatic disease at initial presentation on cranial magnetic resonance imaging; M3, metastatic disease at initial presentation on spinal magnetic resonance imaging, supratent,
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supratentorial
ACCEPTED MANUSCRIPT Table 2: Distribution of metastatic brain lesions within the hippocampal area at initial presentation
Number of metastases
2
Number of patients
2
H <= 5mm 6
5-10 mm 7
2+3 other pts
Mean contribution (%) of metastasis per patient # 12.5%
25%
12.5%
#2
8.3%
16.6%
8.3%
50%
#4
8.3%
#5
8.3%
#8 #9 #10
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#11
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#7
4 other pts
13
50% _
_
100%
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#6
21
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#1
#3
10-15 mm 6
3+4 other pts
Total Number
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H
Rest of the hippocampal area
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First hippocampal area
12.5% 50% 100% 100% 50%
#12
100%
#13
100%
H : hippocampus The number of total metastases was assessed such as individual count from 1 to 5 metastases. Then we defined a group with 5 to 10 metastases (mean : 8) and a group with more than 10 ( mean : 12).
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Hippocampal area
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Hippocampal area + 5 mm
Figure 1 : exemple of hippocampal and perihippocampal area delineation on coronal
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gadolinium contrast-‐enhanced T1-‐weighted acquisitions
S0360-3016(17)34486-3
DOI:
10.1016/j.ijrobp.2017.12.265
Reference:
ROB 24667
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 1 September 2017 Revised Date:
8 November 2017
Accepted Date: 11 December 2017
Please cite this article as: Padovani L, Chapon F, André N, Boucekine M, Geoffray A, Bourdeau F, Masliah-Planchon J, Claude L, Huchet A, Laprie A, Bernard Coche-Dequéant SS, Kerr C, Alapetite C, Leseur J, Nguyen T, Chapet S, Bernier V, Bondiau P-Y, Noel G, Habrand JL, Bolle S, Doz F, Dufour C, Muracciole X, Carrie C, Hippocampal sparing during Craniospinal irradiation, what did we learn about the incidence of peri hippocampus metastases?, International Journal of Radiation Oncology • Biology • Physics (2018), doi: 10.1016/j.ijrobp.2017.12.265. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Hippocampal sparing during Craniospinal irradiation, what did we learn about the incidence of peri hippocampus metastases?
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Laetitia Padovani, Frédérique Chapon, Nicolas André, Mohamed Boucekine, Anne Geoffray, Franck Bourdeau, Julien Masliah-Planchon, Line Claude, Aymeri Huchet, Anne Laprie, Stephane Supiot Bernard Coche-Dequéant, Christine Kerr, Claire Alapetite, Julie Leseur, Tandat Nguyen, Sophie Chapet, Valerie Bernier, Pierre-Yves Bondiau, Georges Noel, Jean Louis Habrand, Stephanie Bolle, François Doz, Christelle Dufour, Xavier Muracciole and Christian Carrie.
APHM Marseille, France (L.P., N.A., X.M.) Faculte Aix –Marseille II ( M.B) Institut Saint Joseph
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Marseille, France (F.C.) CHU Lenval Nice, France (A.G.) (L.C., C.C.) CHU Bordeaux, France (A.H.) IUCT Oncopole Toulouse, France (A.L.) Centre René Gauduchet Nantes, France (S.S) Centre Oscar Lambret
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Lille, France (B.C.-D.) ICM Montpellier, France (C.K.) Institut Curie Paris, France (F.B, C.A., F.D.) PSL Research University, Curie Institute, SiREDO pediatric cancer center & Curie Institute SIRIC, France ( F.B, J.M.P) Centre Eugène Marquis Rennes, France (J.L.) Institut Jean-Godinot Reims, France (T.N) CHU Tours France (S.C.) Centre Alexis Vautrin, France (V.B.) Centre Antoine Lacassagne, (P.Y.B.)Centre Paul Strauss Strasbourg, France (G.N.) Centre Antoine Baclesse Caen, France (J.L.H)
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Institut Gustave Roussy, France (S.B., C.D.) Universite Paris Descartes (F.D)
Corresponding author: laetitia padovani [email protected]
tel +33491384337
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fax +33491385692
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264 Bd jean Moulin 13385 Marseille cedex 5
Responsible for statistical analysis : Mohamed.boucekine [email protected]
264 Bd jean Moulin 13385 Marseille cedex 5 tel +33491384337
Running title: hippocampal metastases in medulloblastoma? Conflict of Interest: no conflict Acknowledgments: The authors thank Victoria Grace for the English writing assistance
ACCEPTED MANUSCRIPT Hippocampal sparing during Craniospinal irradiation, what did we learn about the incidence of peri hippocampus metastases?
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Running title: Hippocampal sparing for high-risk medulloblastoma ?
Summary
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Whole brain irradiation (WBI) plays a role in neurocognitive effects.
New technologies make WBI possible while sparing the hippocampal region (HA-WBI).
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As already done in adult population with primary carcinoma, to safety propose HA-WBI, our study aimed to assess the distribution of brain metastases within the peri hippocampal area (PHA) in high-risk medulloblastoma children.
In conclusion, we recommend to evaluate HA-WBI strategy for subgroup of high risk patients
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without metastatic disease
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ACCEPTED MANUSCRIPT Abstract Background Medulloblastoma represents 20% of pediatric brain tumors. For high-risk medulloblastoma (HRM) patients, the 3- to 5-year event-free survival rate has recently improved from 50% to
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more than 76%. Many survivors, however, experience neurocognitive side effects. Several retrospective studies in patients receiving whole brain irradiation (WBI) suggest a relationship between the radiation dose to the hippocampus and neurocognitive decline. The hippocampal
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avoidance-WBI (HA-WBI) approach could partially reduce neurocognitive impairment in children treated for HRM. We aimed to identify the incidence of patients with peri-
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hippocampal metastases (PHM) to assess the risk of brain relapse when sparing the hippocampal area. Methods
Between 2008 and 2011, 51 patients with HRM were treated according to the French trial
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PNET HR+5. Hippocampal contouring was manually generated in three-dimensional magnetic resonance imaging according to the RTOG 0933 atlas. The distribution of metastases was assessed relative to the hippocampus: 0 to 5 mm for the first perihippocampal
Results
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area (FPHA) and 5 to 15 mm for the rest of perihippocampal area (RPHA)
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The median age of patients was 8.79 years, with 33% being female. After a follow-up of 2.4 years, 43 patients were alive. 28 had brain metastasis at diagnosis and 2 at relapse time with 16% in FPHA and 43% in RPHA. Among 18 patients without brain metastases at diagnosis including M1 patients, none developed secondary lesions within FPHA or RPHA, after receiving 36 Gy No clinical or biological factor was significantly associated with the PHM. Conclusions
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ACCEPTED MANUSCRIPT Our results suggest to evaluate HA-WBI strategy for subgroup of high risk patients without metastatic disease Keywords High-risk medulloblastoma, hippocampal avoidance whole brain radiotherapy, neurocognitive
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effects
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ACCEPTED MANUSCRIPT Introduction Medulloblastoma (MB) accounts for 20% of brain tumors in children and adolescents under the age of 18 years. Approximately one-third of children present with metastases at diagnosis (1). Patients older than 3 years of age with disseminated MB, MB with a residual
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tumor size exceeding 1.5 cm2, or the anaplastic subtype or MB with MYC amplification are considered as high risk (2) In this subgroup of high-risk patients, the three- to five-year event-free survival rate was less than 50% until several years ago, but it has recently
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improved (76%) with the different treatment strategies now available such as high-dose
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chemotherapy (3),hyperfractionated accelerated radiotherapy, use of radiosensitizers and concurrent radiochemotherapy (4)(5)(6).
Many survivors, however, experience neurocognitive side effects such as deterioration in
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attention and executive function, poor working memory, and processing speed dysfunctions. The combination of tumor volume, tumor location, and treatment modalities is responsible for this neurocognitive impact (7)(8). Among the different treatments, whole brain radiotherapy
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plays a significant role in the deterioration of neurocognitive functions (9)(10)(11)(12).
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Preclinical and clinical data confirm that radio-induced neurocognitive toxicity is related to damage to the neural progenitor cells in the subventricular zone and hippocampus (13)(14) as well as vascular injury and glial precursor ablation. Moreover, in a rat model, whole brain radiotherapy led to a reduction in hippocampal volume, the suppression of subventricular zone neurogenesis, the loss of oligodendrocyte precursors (14)(15), and cognitive deficits (16)(15)(17). In addition, several retrospective clinical studies in adult and child populations suggest an association between the radiation dose delivered to the hippocampus and temporal
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ACCEPTED MANUSCRIPT lobes and neurocognitive decline in children treated with whole brain radiotherapy (18)(19)(20).
Modern radiotherapy techniques such as intensity-modulated radiotherapy (IMRT) make
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whole brain irradiation (WBI) possible while sparing the hippocampal region (hippocampalavoiding whole brain irradiation, HA-WBI). This reduced dose to the hippocampal region during WBI could mitigate or prevent neurocognitive impairment. In an adult phase II study
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of the Radiation Therapy Oncology Group (RTOG 0933) involving 113 patients with brain metastases from different primary carcinoma, receiving HA-WBI to 30 Gy in 10 fractions
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Gondi et al. reported a significant decrease in neurocognitive decline compared with historical control and a low incidence (4.5%) of metastases in the avoidance region of HA-WBI among patients with cerebral progression (21).
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The HA-WBI approach has the potential to partially reduce neurocognitive impairment in children with high-risk MB treated with a high-dose of craniospinal radiation provided that there is no increased risk of brain relapse in this region. To date, no study has clearly assessed
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the distribution of brain metastases in the hippocampal region in a high-risk population of children with MB, whether at the time of diagnosis or during progression.
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For this reason, our study aimed to establish retrospectively the incidence of patients with metastases in the hippocampal area before and after craniospinal irradiation in a national cohort of high-risk MB children treated according to the French primitive neuroectodermal tumor (PNET) HR+5 trial. Moreover, we investigated the relationship between clinical parameters and molecular subtypes of MB as well as the risk of peri-hippocampal disease relapse.
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ACCEPTED MANUSCRIPT Materials and Methods Treatment: Between 2009 and 2012, 51 patients aged between 5 and 18 years old with newly diagnosed high-risk medulloblastoma were treated according to the French trial PNET HR+5 protocol:
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Children received as postoperative induction chemotherapy two cycles of etoposide (500mg /m²) - carboplatin (800mg/m²), followed by two courses of thiotepa (600mg/m² per course) with autologous stem cell rescue. Risk-adapted conventional radiotherapy (RT) was delivered
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around day 45 after second transplantation. Craniospinal RT dose was 36 Gy for patients with metastatic disease or with unfavourable histology (anaplastic MB, large cell MB, MB
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with myc amplification) followed by a tumor bed boost of 18 Gy. For localized MB with postoperative residual tumor, RT was consisted of 23.4 Gy on the craniospinal axis and 54 Gy on the primitive tumor. Maintenance treatment with 6 cycles of temozolomide was planned to start between 1-3 months after the end of RT. Pathology samples were centrally reviewed at
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diagnosis according to 2007 WHO classification (Louis, 2007). Subgroup affiliation was established using nanostring targeted gene-expression profiling from paraffin-embedded or frozen samples. Disease status was assessed by MRI of head and spine. If tumor cells were
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identified in the CSF at diagnosis, CSF analysis was also performed until normalization. Tumor response was assessed by independent central review and by investigator using MRI
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and CSF analysis taken at diagnosis, after surgery, before HDCT, after the second HDCT, after RT, every 3 cycles of temozolomide and at the end of treatment. Informed consent was received from parents and/or patients. Approval from Ethics committees was available. The study was registered at the Us National Cancer Institute.
Metastasis distribution:
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ACCEPTED MANUSCRIPT Imaging were investigated during follow up and reviewed again at time of retrospective delineation. Retrospectively, all pre- and post-treatment MRI scans for patients were used to delineate the individual nodular metastases in the perihippocampal area and hippocampus.
RTOG 0933 atlas (22) by a single radiologist physician.
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Hippocampal contouring was manually generated in three-dimensional MRI according to the
(http://www.rtog.org/CoreLab/ContouringAtlases/HippocampalSparing.aspx.
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Contouring was performed on the axial and coronal gadolinium contrast-enhanced T1-
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weighted sequence and, axial T2-weighted and axial and coronal T2 flair images, from anterior to posterior, that is, from the hippocampal head to the tail,. (figure 1) The volume, location, and closest distance of each metastasis to the hippocampus were recorded. Delineation and measurements were performed in radiological department using Review station General Electric advantage windows 4.6. with Advanced software Volume viewer.
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Multimodality contouring..
The distribution of the metastases was assessed relative to the hippocampus: in the
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hippocampus and between 0 and 5 mm, 5 and 10 mm, and 10 and 15 mm from the hippocampus. We define the first part of the hippocampal area between 0 and 10 mm as the
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“first hippocampal area” and the second part from 10 to 15 mm as “the rest of the hippocampal area.” The hippocampal avoidance zones were generated by expanding the hippocampal outlines with margins of 5, 10, and 15 mm volumetrically.
Statistics: Categorical variables are presented as numbers and percentages. The significance of group differences was determined using the chi-square test and Fisher’s exact test, as appropriate. A two-sided p-value >0.05 was considered to indicate statistical significance between patients 7
ACCEPTED MANUSCRIPT with and without hippocampal area lesions according sex, age, type of surgery, histological diagnosis, spinal fluid involvement, biological subgroup, and p53 tumor status.
Results
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51 patients for high-risk MB. The median age was 8.79 years, and 17 were male (33%). Patient characteristics are described in Table 1. Because of deviations, all patients received finally 36 Gy on CSI except 5 patients who received 30.6 Gy whom 3 patients with brain
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metastasis at diagnosis
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Among the 51 patients, except for 3 patients, all diagnosis and follow up MRI including MRI imaging at relapse were available.. 33 patients presented metastases (MRI was available only for 30 in this study): 28 at diagnosis and 2 at the time of progression. Among these 30 patients, 13 children (43%) developed 21 metastases in the perihippocampal area (from
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hippocampus to 15 mm), including 5 patients (16 %) in the first hippocampal area with 2 metastases in the hippocampus and 6 metastases less than 5 mm from it. Among these 5
metastases.
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patients, 3 had more than 10 metastases, 1 had between 5 and 10 metastases, and 1 had only 2
Among the patients with M1 disease at diagnosis, only one had a metastatic relapse; in the
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pituitary area. Only one patient developed a single hippocampal lesion at relapse while he had M3 disease at diagnosis (not shown in the table). No patient with M2 disease at diagnosis developed new brain metastases in perihippocampal area. One of them developed new brain metastasis at relapse: all in posterior fossa while he had only posterior fossa disease at diagnosis. Among the 12 patients without metastatic disease at diagnosis 1 had a metastatic relapse considered outside of the total hippocampal area, with nodules along the lateral ventricles area
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ACCEPTED MANUSCRIPT The spatial distribution of metastatic brain lesions is shown in Table 2.
No clinical factor was found to be significantly associated with perihippocampal metastasis
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distribution.
Discussion
This study is the first to determine the risk of developing perihippocampal metastases to
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assess the potential interest of using HA-WBI for high-risk MB. In this study, among 30 available patients with metastases, 5 children (16%) had metastases in the first hippocampal
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area and 43% in the total hippocampal area. Only one patient (with spinal cord nodules at diagnosis) developed a single hippocampal lesion at relapse. No clinical factor was correlated with the risk of perihippocampal metastases.
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The 16% incidence rate of brain metastases at diagnosis within the perihippocampal region (hippocampus = 5 mm) in our study was very high in comparison with the rate of 4.5% in
(25).
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non-small-cell lung cancer (21), 5% in small-cell lung cancer (24), and 4.1% in breast cancer
In this context, Gondi et al. reported a significant improvement in the memory of patients
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treated with HA-WBI, with only 4.5% of patients (3 out of 67) relapsing in the hippocampal avoidance area (21). In contrast to adult patients treated with whole brain radiotherapy for metastatic disease, the medulloblastoma treatment includes craniospinal radiotherapy plus tumor bed boost irradiation. Although it has not been proven in a randomized trial, pediatric radiation oncologists are now moving away from posterior fossa to tumor bed volume with the aim to reduce the boost volume (26)(27) and decrease the dose delivered to the temporal lobes and hippocampus (7)(28). However, the impact of tumor bed boost on the hippocampus
9
ACCEPTED MANUSCRIPT is not negligible (18)(29). Brodin et al. reported the results of a dosimetric study in 17 pediatric patients with MB to assess the impact of tumor boost dose on the mean hippocampal dose according to the clinical tumor volume (CTV = tumor bed plus margins of 5, 10, and 15 mm, or posterior fossa) and radiotherapy technique: three-dimensional conformal
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radiotherapy, IMRT, and proton therapy (29). They reported statistically significant correlations between the size of the planned target volume (PTV = CTV plus 5 mm) and the mean hippocampal dose. They also showed that IMRT can add 6.9, 9.5, and 11.8 Gy to the
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hippocampal dose according to margins of 5, 10, and 15 mm around the tumor bed, respectively. Proton therapy would be able to limit this hippocampal boost dose to 3.3, 6.1,
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and 8.7 Gy using the same respective margins.
Different studies have analyzed the quality of PTV coverage in HA-WBI and the level of the decreased dose delivered to the hippocampal region. Gondi et al. reported the PTV coverage
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and hippocampus dose in five patients treated with HA-WBI delivered at 30 Gy in 10 fractions. With an hippocampal avoidance area as hippocampus volume plus 5 mm, the mean dose (normalized to 2 Gy fractions) received by the hippocampus ranged between 4.9 and 7.3
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Gy, with a maximum dose between 12.8 and 15.3 Gy for a PTV coverage between 93 and 95% (22). For the craniospinal part of medulloblastoma irradiation, HA-WBI decreases the
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hippocampal dose by around 15% using IMRT, while the brain coverage was relaxed from 98 to 95% (29).
In a dosimetric feasibility study of hippocampal sparing in patients treated for MB, Blomstrand et al. estimated that the frequency of adverse neurological effects could be dramatically reduced (30) Brodin et al. also investigated hippocampal sparing with IMRT during focal boost radiotherapy, which induces a considerable estimated clinical benefit using a dose-response model (29).
10
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One of the major questions related to this study remains unanswered: what is the dose threshold below which hippocampal stem cell neurogenesis is preserved and which dose is clinically relevant for the pediatric patient in terms of decreased neurocognitive side effects?
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Merchant et al. reported that increasing mean doses to hippocampi had a significant negative impact on estimated intellectual quotient, reading, and spelling in children, with a younger age at the time of irradiation amplifying this impact (6). Yet, no threshold in terms of dose or
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volume could be identified as a target for the HA-WBI approach. Several studies have reported different threshold founded correlated with neurocognitive improvement such as less
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than 7.3 Gy to 40% of bilateral hippocampi (31), maximal dose of 9 Gy to 100% of hippocampi (20) or maximal dose of 5.83 to 100% of the bilateral hippocampal in an adult study (32)
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Regarding our limited knowledge, it seems that for medulloblastoma, the maximal dose to hippocampus should be at least less than 5Gy for craniospinal treatment while taking into account the additional tumor boost dose estimated at around 9 Gy using IMRT (29). For this
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reason, we advocate defining the perihippocampal area as the hippocampus plus 10 to 15 mm
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to be able to correctly decrease the total hippocampal dose.
In our study, the 16% incidence rate of hippocampal metastases in the first area and 43% from the hippocampus to 15 mm should be considered as high rates. Based on the results of the quality control of radiotherapy in MB, which significantly reduced the incidence of frontal recurrence (33), the risk of recurrence in these perihippocampal regions with a high gradient dose resulting from HA-WBI could increase substantially. Our study results do not encourage
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ACCEPTED MANUSCRIPT the use of craniospinal irradiation with hippocampal sparing for children with metastatic medulloblastoma. However, among 18 available patients without brain metastases at diagnosis including M1 patients, only 2 developed brain metastases and out of hippocampi area, after receiving 36 Gy.
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These results indicate that hippocampi sparing technique for craniospinal irradiation in high risk no metastatic medulloblastoma patients could be prospectively investigated
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The size of population could not allow us to identify molecular groups that were significantly associated with a very low risk of perihippocampal metastases. However, in 2013,
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Ramaswamy et al. reported very rarely distant metastasis in atients in the SHH group while group 3 and 4 patients developed a recurrence of brain metastases independently of treatment effect (33). In our series, seven patients were classified in the SHH group, including three patients with positive p53 status. Two presented multiple brain metastases at diagnosis, all
patients.
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with perihippocampal lesions. No brain or spinal metastasis was observed for p53-negative
Indeed, a sample of high-risk MB patients treated without radiotherapy could be an interesting
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population to study in order to assess the real risk of perihippocampal relapse. This discussion could also be extended to average-risk medulloblastoma patients and low risk
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medulloblastoma where focusing on hippocampal avoidance could be an interesting alternative to global decrease in doses. Other therapeutic strategies attempt to decrease the neurocognitive impairment of radiotherapy with some promising results yet to be confirmed, such as hyperfractionated radiotherapy (34)(35), protontherapy (36), and pharmacological interventions. (8)
Conclusion 12
ACCEPTED MANUSCRIPT If the overall incidence of patients with brain metastases in the hippocampal area before craniospinal irradiation in the metastatic medulloblastoma subgroup is elevated, and does not support hippocampi sparing at this time. In opposite, the lack of hippocampi area relapse among high risk patients without metastatic disease in our study suggest that this group may
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benefit from hippoacmapi sparing prospective investigation . This national French sample, however, needs to be increased in order to confirm the subgroups of patients available for
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HA-WBI.
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2. Polkinghorn WR, Tarbell NJ. Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nat Clin Pract Oncol. 2007 May;4(5):295–304.
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ACCEPTED MANUSCRIPT 12. Sun A, Bae K, Gore EM, Movsas B, Wong SJ, Meyers CA, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol Off J Am Soc Clin Oncol. 2011 Jan 20;29(3):279–86.
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15. Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursorcell dysfunction. Nat Med. 2002 Sep;8(9):955–62.
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16. Tada E, Parent JM, Lowenstein DH, Fike JR. X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats. Neuroscience. 2000;99(1):33–. 17. Parent JM, Tada E, Fike JR, Lowenstein DH. Inhibition of dentate granule cell neurogenesis with brain irradiation does not prevent seizure-induced mossy fiber synaptic reorganization in the rat. J Neurosci Off J Soc Neurosci. 1999 Jun 1;19(11):4508–19. 18. Armstrong GT, Jain N, Liu W, Merchant TE, Stovall M, Srivastava DK, et al. Regionspecific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies. Neuro-Oncol. 2010 Nov;12(11):1173–86.
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ACCEPTED MANUSCRIPT Neuropsychological Outcome of Children Treated for Standard Risk Medulloblastoma in the PNET4 European Randomized Controlled Trial of Hyperfractionated Versus Standard Radiation Therapy and Maintenance Chemotherapy. Int J Radiat Oncol Biol Phys. 2015 Aug 1;92(5):978–85.
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ACCEPTED MANUSCRIPT Table 1: Patient characteristics Caracteristics
Number of patients (%)
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Male Ventriculoperitoneal shunt Ventriculoventricular shunt External shunt Extent of resection, including second surgery Total Partial Biopsy
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28 9 10 4
Biological group WNT SHH p53-/SHH p53+ 3 4 Undetermined
3 4/3 15 15 11
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Isolated M1 Non-isolated M1
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Initial presentation and relapse time M2 M3 M2/M3
47 3 1
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Histologic subtype CMB DMB LC/A MB Unclassifiable
M0 patients
34 6 22 4
12 6 8 30 16 9 5
Unavailable MRI
3
M1non isolated
1
M3
1
Unknown
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Female
1
Survival Alive
43
Dead
8
Abbreviations: M1, presence of tumor cells in the CSF at diagnosis; M2, metastatic disease at initial presentation on cranial magnetic resonance imaging; M3, metastatic disease at initial presentation on spinal magnetic resonance imaging, supratent,
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supratentorial
ACCEPTED MANUSCRIPT Table 2: Distribution of metastatic brain lesions within the hippocampal area at initial presentation
Number of metastases
2
Number of patients
2
H <= 5mm 6
5-10 mm 7
2+3 other pts
Mean contribution (%) of metastasis per patient # 12.5%
25%
12.5%
#2
8.3%
16.6%
8.3%
50%
#4
8.3%
#5
8.3%
#8 #9 #10
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#11
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#7
4 other pts
13
50% _
_
100%
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#6
21
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#1
#3
10-15 mm 6
3+4 other pts
Total Number
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H
Rest of the hippocampal area
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First hippocampal area
12.5% 50% 100% 100% 50%
#12
100%
#13
100%
H : hippocampus The number of total metastases was assessed such as individual count from 1 to 5 metastases. Then we defined a group with 5 to 10 metastases (mean : 8) and a group with more than 10 ( mean : 12).
RI PT
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Hippocampal area
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Hippocampal area + 5 mm
Figure 1 : exemple of hippocampal and perihippocampal area delineation on coronal
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gadolinium contrast-‐enhanced T1-‐weighted acquisitions