Publications by authors named "Stephanie Bolle"

50 Publications

Head and neck tumors in children and adolescents: Impact of a multidisciplinary tumor board.

Oral Oncol 2021 Jan 20;114:105145. Epub 2021 Jan 20.

Pediatric Ear, Nose, and Throat Department, Robert Debré Hospital, Public Assistance-Hospitals of Paris, Paris, France.

Introduction: Cancer treatment in France is based on Multidisciplinary Tumor Board (MTB). In the Ile-de-France region (IDF), which includes 12 million inhabitants from Paris and the surrounding area, pediatric tumors of head and neck are discussed since 2013 in a dedicated Interregional Pediatric Multicentric MTB (IPMTB). The purpose of this study is to analyze the impact of the IDF head and neck IPMTB on the management of these tumors, 5 years after their implementation.

Materials And Methods: Retrospective study of all patient files presented in the IPMTB for a benign or malignant head-and-neck tumor, between 2013 and 2018.

Results: A total of 679 discussions were analyzed representing 428 patients. Median age was 7.5 years (range: 0-31 years). Malignant tumors represented 71% of cases, including 36% of rhabdomyosarcoma. Overall, 12% percent of the cases discussed came from centers outside of IDF. All meetings complied with multidisciplinary criteria required by French law. Proposals made during the IPMTB were followed in 86% of cases. Among the 251 proposals made by the referring teams prior to the IPMTB, 29% were secondarily modified after being discussed in the IPMTB.

Conclusion: Thanks to their multidisciplinarity, high number of cases discussed and usual respect of their proposals, the IPMTB have made it possible to improve the coordination between all specialties involved in the patient's management, to apply the most recent and scientifically validated protocols, and to share the knowledge of different teams concerning the management of particularly rare tumors.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105145DOI Listing
January 2021

Radical radiotherapy for paediatric solid tumour metastases: An overview of current European protocols and outcomes of a SIOPE multicenter survey.

Eur J Cancer 2021 Jan 15;145:121-131. Epub 2021 Jan 15.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands; Princess Máxima Center for Paediatric Oncology, Utrecht, The Netherlands.

Purpose/objective: About 20% of children with solid tumours (ST) present with distant metastases (DM). Evidence regarding the use of radical radiotherapy of these DM is sparse and open for personal interpretation. The aim of this survey was to review European protocols and to map current practice regarding the irradiation of DM across SIOPE-affiliated countries.

Materials/methods: Radiotherapy guidelines for metastatic sites (bone, brain, distant lymph nodes, lung and liver) in eight European protocols for rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma, Ewing sarcoma, neuroblastoma and renal tumours were reviewed. SIOPE centres irradiating ≥50 children annually were invited to participate in an online survey.

Results: Radiotherapy to at least one metastatic site was recommended in all protocols, except for high-risk neuroblastoma. Per protocol, dose prescription varied per site, and information on delineation and treatment planning/delivery was generally missing. Between July and September 2019, 20/27 centres completed the survey. Around 14% of patients were deemed to have DM from ST at diagnosis, of which half were treated with curative intent. A clear cut-off for a maximum number of DM was not used in half of the centres. Regardless of the tumour type and site, conventional radiotherapy regimens were most commonly used to treat DM. When stereotactic radiotherapy was used, a wide range of fractionation regimens were applied.

Conclusion: Current radiotherapy guidelines for DM do not allow a consistent approach in a multicentre setting. Prospective (randomised) trials are needed to define the role of radical irradiation of DM from paediatric ST.
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http://dx.doi.org/10.1016/j.ejca.2020.12.004DOI Listing
January 2021

High-dose proton therapy and tomotherapy for the treatment of sacral chordoma: a retrospective monocentric study.

Acta Oncol 2021 Feb 23;60(2):245-251. Epub 2020 Oct 23.

Department of Radiation Oncology, Proton Therapy Centre, Curie Institute, Orsay, France.

Objective: Radiation therapy (RT) is used for the treatment of sacral chordoma, in combination with surgery or alone for unresected tumours, to improve local control (LC) and potentially overall survival (OS). The purpose of the present study was to evaluate efficacy and toxicity of proton therapy (PT), and/or intensity modulated radiation therapy (IMRT), particularly Tomotherapy, for sacral chordoma treatment. Between November 2005 and June 2018, 41 consecutive patients who were not included in clinical trials, received sacral chordoma radiation treatment in Institut Curie with Tomotherapy alone in 13 patients, and combined PT and Tomotherapy boost (Proton - Tomo) in 28 patients. RT was delivered as the exclusive local treatment in 11 patients, and as a post-operative complementary treatment in 30 patients.

Results: After a median follow-up of 46 months (range, 0-125 months), eight local relapses were observed, and seven patients developed distant metastasis (particularly bone and lung). The 2- and 5- year local relapse rates were 11.4% CI (0.65-22.2%) and 29% (10.5-47.4%), respectively. Over the follow-up period, ten patients died (24.4%). The estimated 2- and 5-year OS rates were 91.4% CI (82.5-100%) and 74.5% (59.4-93.5%), respectively. Fibrosis, syndrome, and pain were the most common late toxicities. The comparison between Tomotherapy alone and Proton - Tomo revealed that acute and late cystitis were significantly more frequent in the Tomotherapy group: SHR = 0.12 IC95% (0.01-0.90 [ = .04]), as well as late proctitis. A dosimetric comparison confirmed the interest of PT to spare rectum and bladder in this context.

Conclusion: RT remains essential to improve local control in sacral chordoma. The combination of proton and photon seems to improve organ at risk sparing, resulting in a decreased rate of reported late toxicities.
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http://dx.doi.org/10.1080/0284186X.2020.1834140DOI Listing
February 2021

The SIOP-Renal Tumour Study Group consensus statement on flank target volume delineation for highly conformal radiotherapy.

Lancet Child Adolesc Health 2020 11;4(11):846-852

Department of Radiation Oncology, Saarland University Hospital, Homburg, Germany.

For decades, radiotherapy with two opposing photon beams has been the standard technique used to cover the flank target volume in paediatric patients with renal tumours. Nowadays, many institutes are implementing advanced radiotherapy techniques that spare healthy tissue. To decrease the radiotherapy dose to healthy structures while preserving oncological efficacy, the conventional approach of flank irradiation has been adapted into a guideline for highly conformal flank target-volume delineation by paediatric radiation oncologists and representatives of the International Society of Paediatric Oncology's Renal Tumour Study Group (SIOP-RTSG) board during four live international consensus meetings. The consensus was refined by delineation exercises and videoconferences by ten collaborating paediatric radiation oncologists. The final guideline includes eight chronological steps to generate the tumour bed and clinical, internal, and planning target volumes, and it describes the optional use of surgical clips to optimise treatment planning. This guideline will be added into the radiotherapy guideline of the UMBRELLA SIOP-RTSG protocol for paediatric renal tumours to improve international consistency of highly conformal flank target-volume delineation.
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http://dx.doi.org/10.1016/S2352-4642(20)30183-8DOI Listing
November 2020

Risk Factors of Subsequent Central Nervous System Tumors after Childhood and Adolescent Cancers: Findings from the French Childhood Cancer Survivor Study.

Cancer Epidemiol Biomarkers Prev 2021 Jan 8;30(1):133-141. Epub 2020 Oct 8.

Inserm U1018, CESP, Radiation Epidemiology Team, Gustave Roussy, Villejuif, Paris, France.

Background: Childhood or adolescent cancer survivors are at increased risks of subsequent primary neoplasms (SPN) of the central nervous system (CNS) after cranial irradiation. In a large multicentric cohort, we investigated clinical and therapeutic factors associated with the long-term risk of CNS SPN, and quantified the dose-response relationships.

Methods: We selected all CNS SPN cases diagnosed up to 2016 among members of the French Childhood Cancer Survivor Study at least 5 years after first cancer diagnosis in 1946-2000. Four controls per case were randomly selected within the cohort and matched by sex, year of/age at first cancer diagnosis, and follow-up time. On the basis of medical and radiological reports, cumulative radiation doses received to the SPN or matched location were retrospectively estimated using mathematical phantoms. We computed conditional logistic regression models.

Results: Meningioma risk significantly increased with higher radiation doses [excess OR per Gy (EOR/Gy) = 1.377; < 0.001; 86 cases; median latency time = 30 years], after adjustment for reported genetic syndromes and first CNS tumor. It was higher among youngest individuals at first cancer diagnosis, but did not vary with follow-up time. On the opposite, radiation-related glioma risk (EOR/Gy = 0.049; = 0.11; 47 cases; median latency time = 17 years) decreased over time ( for time effect = 0.05). There was a significant association between meningioma risk and cumulative doses of alkylating agents, but no association with growth hormone therapy.

Conclusions: The surveillance of patients with cranial irradiation should continue beyond 30 years after treatment.

Impact: The identified risk factors may inform long-term surveillance strategies.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0735DOI Listing
January 2021

Second-line therapy in young patients with relapsed or refractory orbital rhabdomyosarcoma.

Acta Ophthalmol 2020 Aug 24. Epub 2020 Aug 24.

SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Institut Curie, PSL University, Paris, France.

Objective: Localized orbital rhabdomyosarcoma (oRMS) has an overall favourable prognosis with more than 90% of survival. Little is known about the best strategy in recurrent/refractory (R/R) cases. The purpose is to examine the characteristics of patients with R/R-oRMS, focusing on local therapy.

Methods: This is bicentric retrospective study. Analysis is of young patients (<30 years) with R/R-oRMS who were treated from 1989 to 2018 at the Institut Curie and Gustave Roussy Cancer Campus, France.

Results: Twenty-seven out of 162 patients (17%) with oRMS presented with R/R disease. 6 of these patients had alveolar RMS (22%), 3 of whom had initial parameningeal extension (11%). During first-line treatment, 18 patients (67%) had orbital radiotherapy. Median age at R/R was 10 years (ranges: 4-28) after a delay of 19 months from diagnosis (ranges: 3-40). Tumoral events were local relapses (22 cases), local progression (3 cases) or regional relapses (2 cases). Second-line treatments included chemotherapy (27 cases), radiotherapy (16 cases), surgery (exenteration; 8 cases) and metastasis/ nodal removal (3 cases). After a median follow-up of 99 months (range: 10-306), 4 patients died and 23 are in complete remission (CR) without treatment. One patient had subsequent relapse treated with exenteration and brachytherapy until a new tumour remission. Five-year event-free and overall survivals after first tumour event are, respectively, 84.4% (95% confidence interval: 71.5%-98.8%) and 85.8% (95% confidence interval: 72.1%-100.0%) CONCLUSION: R/R-oRMS is a rare situation. Second-line therapy is efficient in this location, sometime at the cost of lifesaving mutilating surgery. Second-line local therapy needs therefore to consider local radiotherapy if possible or complete wide surgery.
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http://dx.doi.org/10.1111/aos.14596DOI Listing
August 2020

Analysis of Radiation Dose/Volume Effect Relationship for Anorectal Morbidity in Children Treated for Pelvic Malignancies.

Int J Radiat Oncol Biol Phys 2021 Jan 14;109(1):231-241. Epub 2020 Aug 14.

Department of Radiation Oncology, Gustave Roussy Cancer Campus, Cancer Center, University Paris Saclay Medical Faculty, Villejuif, France; INSERM 1030 Molecular radiotherapy, Gustave Roussy Cancer Campus, Villejuif, France; French Military Health Academy, Ecole du Val-de-Grâce, Paris, France; Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France. Electronic address:

Purpose: To examine dose-volume effect relationships for anorectal morbidity in children treated with image-guided brachytherapy for pelvic tumors.

Methods And Materials: Medical records of all consecutive children with pelvic tumors treated in our center and receiving image-guided pulsed-dose-rate brachytherapy with or without external beam radiation therapy (EBRT) between 2005 and 2019 were reviewed. The effect of the minimal doses to the most exposed 0.5 cm, 1 cm, and 2 cm of the anorectum (respectively: D, D, and D), total reference air kerma (TRAK), and volume of 100% isodose was examined for anorectal toxicities.

Results: Seventy-eight consecutive children were included. Median age was 2.9 years (range, 0.8-14.9 years). Most of the tumors were bladder or prostate (67%) or vaginal (22%) rhabdomyosarcoma. Six patients received EBRT in addition to brachytherapy. Median follow-up was 21.3 months. At last follow-up, 30 children (38%) had experienced Common Terminology Criteria for Adverse Events version 5 grade ≥1 acute or late anorectal events: 24% had grade 1 events, 7.7% had grade 2 events, and 6.4% had grade 3 events. No toxicity greater than grade 3 was observed (eg, fistula or stricture). In univariate analysis, the D and D were significant for probability of grade 1 to 3 (P = .009 and P = .017, respectively) and grade 2 to 3 anorectal morbidity (P = .007 and P = .049, respectively). There was no significant correlation for D (P = .057 for grade 1-3; P = .407 for grade 2-3). A 10% probability (95% confidence interval, 4%-20%) for anorectal toxicity of grade 2 or greater was reached for a D = 52 Gy. The age, EBRT use, TRAK, and treated volume values were not significant.

Conclusions: To our knowledge, this study is the first to show a significant dose-volume effect relationships for anorectal morbidity in children undergoing treatment with brachytherapy. Integrating these data into brachytherapy treatment planning could help to optimize the therapeutic index in these young patients.
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http://dx.doi.org/10.1016/j.ijrobp.2020.08.033DOI Listing
January 2021

Exclusive Hyperfractionated Radiation Therapy and Reduced Boost Volume for Standard-Risk Medulloblastoma: Pooled Analysis of the 2 French Multicentric Studies MSFOP98 and MSFOP 2007 and Correlation With Molecular Subgroups.

Int J Radiat Oncol Biol Phys 2020 Dec 6;108(5):1204-1217. Epub 2020 Aug 6.

Department of Radiotherapy, CHU La Timone, AP-HM, Marseille, France.

Purpose: Medulloblastoma has recently been characterized as a heterogeneous disease with 4 distinct molecular subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4, with a new definition of risk stratification. We report progression-free survival, overall survival, and long-term cognitive effects in children with standard-risk medulloblastoma exclusively treated with hyperfractionated radiation therapy (HFRT), reduced boost volume, and online quality control, and we explore the prognostic value of biological characteristics in this chemotherapy-naïve population.

Methods And Materials: Patients with standard-risk medulloblastoma were enrolled in 2 successive prospective multicentric studies, MSFOP 98 and MSFOP 2007, and received exclusive HFRT (36 Gy, 1 Gy/fraction twice daily) to the craniospinal axis followed by a boost at 68 Gy restricted to the tumor bed (1.5 cm margin), with online quality assurance before treatment. Patients with MYC or MYCN amplification were not excluded at the time of the study. We report progression-free survival and overall survival in the global population, and according to molecular subgroups as per World Health Organization 2016 molecular classification, and we present cognitive evaluations based on the Wechsler scale.

Results: Data from 114 patients included in the MSFOP 98 trial from December 1998 to October 2001 (n = 48) and in the MSFOP 2007 from October 2008 to July 2013 (n = 66) were analyzed. With a median follow-up of 16.2 (range, 6.4-19.6) years for the MSFOP 98 cohort and 6.5 (1.6-9.6) years for the MSFOP 2007 cohort, 5-year overall survival and progression-free survival in the global population were 84% (74%-89%) and 74% (65%-81%), respectively. Molecular classification was determined for 91 patients (WNT [n = 19], SHH [n = 12], and non-WNT/non-SHH [n = 60]-including group 3 [n = 9], group 4 [n = 29], and not specified [n = 22]). Our results showed more favorable outcome for the WNT-activated subgroup and a worse prognosis for SHH-activated patients. Three patients had isolated extra-central nervous system relapse. The slope of neurocognitive decline in the global population was shallower than that observed in patients with a normofractionated regimen combined with chemotherapy.

Conclusions: HFRT led to a 5-year survival rate similar to other treatments combined with chemotherapy, with a reduced treatment duration of only 6 weeks. We confirm the MSFOP 98 results and the prognostic value of molecular status in patients with medulloblastoma, even in the absence of chemotherapy. Intelligence quotient was more preserved in children with medulloblastoma who received exclusive HFRT and reduced local boost, and intelligence quotient decline was delayed compared with patients receiving standard regimen. HFRT may be appropriate for patients who do not consent to or are not eligible for prospective clinical trials; for patients from developing countries for whom aplasia or ileus may be difficult to manage in a context of high cost/effectiveness constraints; and for whom shortened duration of RT may be easier to implement.
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http://dx.doi.org/10.1016/j.ijrobp.2020.07.2324DOI Listing
December 2020

Influence of growth hormone therapy on the occurrence of a second neoplasm in survivors of childhood cancer.

Eur J Endocrinol 2020 Oct;183(4):471-480

Cancer and Radiation, CESP, Unit 1018 INSERM, Villejuif, France.

Context: Growth hormone (GH) deficiency is a common late effect of cranial irradiation. However, concerns have been raised that GH treatment might lead to an increased risk of a second neoplasm (SN).

Objective: To study the impact of GH treatment on the risk of SN in a French cohort of survivors of childhood cancer (CCS) treated before 1986.

Design And Setting: Cohort study and nested case-control study.

Participants: Of the 2852 survivors, with a median follow-up of 26 years, 196 had received GH therapy (median delay from cancer diagnosis: 5.5 years).

Main Outcome Measures: Occurrence of SN.

Results: In total, 374 survivors developed a SN, including 40 who had received GH therapy. In a multivariate analysis, GH treatment did not increase the risk of secondary non-meningioma brain tumors (RR: 0.6, 95% CI: 0.2-1.5, P = 0.3), secondary non-brain cancer (RR: 0.7, 95% CI: 0.4-1.2, P = 0.2), or meningioma (RR: 1.9, 95% CI: 0.9-4, P = 0.09). Nevertheless, we observed a slight non-significant increase in the risk of meningioma with GH duration: 1.6-fold (95% CI: 1.2-3.0) after an exposure of less than 4 years vs 2.3-fold (95% CI: 0.9-5.6) after a longer exposure (P for trend = 0.07) confirmed by the results of a case-control study.

Conclusion: This study confirms the overall safety of GH use in survivors of childhood cancer, which does not increase the risk of a SN. The slight excess in the risk of meningioma in patients with long-term GH treatment is non-significant and could be due to difficulties in adjustment on cranial radiation volume/dose and/or undiagnosed meningioma predisposing conditions.
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http://dx.doi.org/10.1530/EJE-20-0369DOI Listing
October 2020

Testicular transposition in children before scrotal external radiotherapy.

Pediatr Blood Cancer 2020 09 2;67(9):e28526. Epub 2020 Jul 2.

Radiation Oncology Department, Centre Léon Bérard, Lyon, France.

Testicular transposition (TT) before scrotal external radiotherapy (RT) is poorly reported in children with cancer, with only rare case reports published. TT surgical techniques, dosimetric parameters, and testicular functions are retrospectively reported in 12 children, median age 12.8 years, after scrotal RT for sarcomas. TT has low morbidity and allows a dramatic RT dose decrease in the healthy testicle. Endocrine functions seem preserved while more follow-up is needed to assess fertility. Though a rare situation, TT should be discussed in children and young adult cases when a scrotal high-dose RT is needed.
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http://dx.doi.org/10.1002/pbc.28526DOI Listing
September 2020

Role of neoadjuvant chemotherapy in metastatic medulloblastoma: a comparative study in 92 children.

Neuro Oncol 2020 11;22(11):1686-1695

Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France.

Background: Previous pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits and risks compared with initial surgery have not been assessed.

Methods: Two therapeutic strategies were retrospectively compared in 92 patients with metastatic medulloblastoma treated at Gustave Roussy between 2002 and 2015: surgery at diagnosis (n = 54, group A) and surgery delayed after carboplatin and etoposide-based neoadjuvant therapy (n = 38, group B). Treatment strategies were similar in both groups.

Results: The rate of complete tumor excision was significantly higher in group B than in group A (93.3% vs 57.4%, P = 0.0013). Postoperative complications, chemotherapy-associated side effects, and local progressions were not increased in group B. Neoadjuvant chemotherapy led to a decrease in the primary tumor size in all patients; meanwhile 4/38 patients experienced a distant progression. The histological review of 19 matched tumor pairs (before and after chemotherapy) showed that proliferation was reduced and histological diagnosis feasible and accurate even after neoadjuvant chemotherapy. The 5-year progression-free and overall survival rates were comparable between groups. Comparison of the longitudinal neuropsychological data showed that intellectual outcome tended to be better in group B (the mean predicted intellectual quotient value was 6 points higher throughout the follow-up).

Conclusion: Preoperative chemotherapy is a safe and efficient strategy for metastatic medulloblastoma. It increases the rate of complete tumor excision and may improve the neuropsychological outcome without jeopardizing survival.

Key Points: 1. Preoperative chemotherapy increases the rate of complete tumor removal.2. No additional risk (toxic or disease progression) is linked to the delayed surgery.3. Preoperative chemotherapy could have a positive impact on the neuropsychological outcome of patients.
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http://dx.doi.org/10.1093/neuonc/noaa083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846143PMC
November 2020

Risk Factors for Small Adult Height in Childhood Cancer Survivors.

J Clin Oncol 2020 06 20;38(16):1785-1796. Epub 2020 Mar 20.

Cancer and Radiation Team, Center for Research in Epidemiology and Population Health, INSERM U1018, Villejuif, France.

Purpose: Between 10% and 20% of childhood cancer survivors (CCS) experience impaired growth, leading to small adult height (SAH). Our study aimed to quantify risk factors for SAH or growth hormone deficiency among CCS.

Methods: The French CCS Study holds data on 7,670 cancer survivors treated before 2001. We analyzed self-administered questionnaire data from 2,965 CCS with clinical, chemo/radiotherapy data from medical records. SAH was defined as an adult height ≤ 2 standard deviation scores of control values obtained from a French population health study.

Results: After exclusion of 189 CCS treated with growth hormone, 9.2% (254 of 2,776) had a SAH. Being young at the time of cancer treatment (relative risk [RR], 0.91 [95% CI, 0.88 to 0.95] by year of age), small height at diagnosis (≤ 2 standard deviation scores; RR, 6.74 [95% CI, 4.61 to 9.86]), pituitary irradiation (5-20 Gy: RR, 4.24 [95% CI, 1.98 to 9.06]; 20-40 Gy: RR, 10.16 [95% CI, 5.18 to 19.94]; and ≥ 40 Gy: RR, 19.48 [95% CI, 8.73 to 43.48]), having received busulfan (RR, 4.53 [95% CI, 2.10 to 9.77]), or > 300 mg/m of lomustine (300-600 mg/m: RR, 4.21 [95% CI, 1.61 to 11.01] and ≥ 600 mg/m: RR, 9.12 [95% CI, 2.75 to 30.24]) were all independent risk factors for SAH. Irradiation of ≥ 7 vertebrae (≥ 15 Gy on ≥ 90% of their volume) without pituitary irradiation increased the RR of SAH by 4.62 (95% CI, 2.77 to 7.72). If patients had also received pituitary irradiation, this increased the RR by an additional factor of 1.3 to 2.4.

Conclusion: CCS are at a high risk of SAH. CCS treated with radiotherapy, busulfan, or lomustine should be closely monitored for growth, puberty onset, and potential pituitary deficiency.
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http://dx.doi.org/10.1200/JCO.19.02361DOI Listing
June 2020

TP53 Pathway Alterations Drive Radioresistance in Diffuse Intrinsic Pontine Gliomas (DIPG).

Clin Cancer Res 2019 11 3;25(22):6788-6800. Epub 2019 Sep 3.

UMR8203, "Vectorologie & Thérapeutiques Anticancéreuses," CNRS, Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.

Purpose: Diffuse intrinsic pontine gliomas (DIPG) are the most severe pediatric brain tumors. Although accepted as the standard therapeutic, radiotherapy is only efficient transiently and not even in every patient. The goal of the study was to identify the underlying molecular determinants of response to radiotherapy in DIPG.

Experimental Design: We assessed response to ionizing radiations in 13 different DIPG cellular models derived from treatment-naïve stereotactic biopsies reflecting the genotype variability encountered in patients at diagnosis and correlated it to their principal molecular alterations. Clinical and radiologic response to radiotherapy of a large cohort of 73 DIPG was analyzed according to their genotype. Using a kinome-wide synthetic lethality RNAi screen, we further identified target genes that can sensitize DIPG cells to ionizing radiations.

Results: We uncover mutation as the main driver of increased radioresistance and validated this finding in four isogenic pairs of DIPG cells with or without knockdown. In an integrated clinical, radiological, and molecular study, we show that DIPG patients respond less to irradiation, relapse earlier after radiotherapy, and have a worse prognosis than their counterparts. Finally, a kinome-wide synthetic lethality RNAi screen identifies CHK1 as a potential target, whose inhibition increases response to radiation specifically in cells.

Conclusions: Here, we demonstrate that mutations are driving DIPG radioresistance both in patients and corresponding cellular models. We suggest alternative treatment strategies to mitigate radioresistance with CHK1 inhibitors. These findings will allow to consequently refine radiotherapy schedules in DIPG.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0126DOI Listing
November 2019

Feasibility of Dose Escalation in Patients With Intracranial Pediatric Ependymoma.

Front Oncol 2019 21;9:531. Epub 2019 Jun 21.

ToNIC, Toulouse NeuroImaging Center, Universite de Toulouse, Inserm, Toulouse, France.

Pediatric ependymoma carries a dismal prognosis, mainly owing to local relapse within RT fields. The current prospective European approach is to increase the radiation dose with a sequential hypofractionated stereotactic boost. In this study, we assessed the possibility of using a simultaneous integrated boost (SIB), comparing VMAT vs. IMPT dose delivery. The cohort included 101 patients. The dose to planning target volume (PTV59.4) was 59.4/1.8 Gy, and the dose to SIB volume (PTV67.6) was 67.6/2.05 Gy. Gross tumor volume (GTV) was defined as the tumor bed plus residual tumor, clinical target volume (CTV59.4) was GTV + 5 mm, and PTV59.4 was CTV59.4 + 3 mm. PTV67.6 was GTV+ 3 mm. After treatment plan optimization, quality indices and doses to target volume and organs at risk (OARs) were extracted and compared with the standard radiation doses that were actually delivered (median = 59.4 Gy [50.4 59.4]). In most cases, the proton treatment resulted in higher quality indices ( < 0.001). Compared with the doses that were initially delivered, mean, and maximum doses to some OARs were no higher with SIB VMAT, and significantly lower with protons ( < 0.001). In the case of posterior fossa tumor, there was a lower dose to the brainstem with protons, in terms of V59 Gy, mean, and near-maximum (D2%) doses. Dose escalation with intensity-modulated proton or photon SIB is feasible in some patients. This approach could be considered for children with unresectable residue or post-operative FLAIR abnormalities, particularly if they have supratentorial tumors. It should not be considered for infratentorial tumors encasing the brainstem or extending to the medulla.
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http://dx.doi.org/10.3389/fonc.2019.00531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598548PMC
June 2019

[Treatment of mucositis pain: News and prospects].

Bull Cancer 2019 Sep 6;106(9):776-783. Epub 2019 Jun 6.

Université Paris-Saclay, Gustave Roussy, centre d'études et de traitement de la douleur, 94805 Villejuif, France. Electronic address:

Mucositis, an acute inflammation of the digestive mucosa, is one of the main toxicities secondary to oncological treatments. Among its consequences, mucositis-related pain is an important complication due to its intensity and repercussion, especially on quality of life. Treatment of pain plays a central role in management of mucositis. It must be multimodal, combining local and general opioid or non-opioid treatments, adapted to pain intensity and based on international recommendations updated in 2014. A systemic analgesic treatment with morphine with a patient-controlled analgesia device is often necessary in severe mucositis. In case of insufficient analgesia, use of co-analgesics (paracetamol, ketamine, anticonvulsants, and antidepressants) can improve analgesic control and reduce morphine doses. Non-drug strategies (distraction, relaxation, hypnosis) and preventive measures must be a major concern. Among them, laser therapy using a low power athermal laser beam, is a promising therapeutic strategy whose effectiveness is based on its analgesic, anti-inflammatory, and healing properties. Despite many available studies, there is a limited number of clinically effective therapies. New therapeutic agents for the prevention and treatment of mucositis and its pain, based on the biological phenomena involved, must be further developed to improve the efficacy of analgesia.
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http://dx.doi.org/10.1016/j.bulcan.2019.03.022DOI Listing
September 2019

Adapted strategy to tumor response in childhood nasopharyngeal carcinoma: the French experience.

Strahlenther Onkol 2019 Jun 8;195(6):504-516. Epub 2019 Apr 8.

SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with cancer), PSL Research University, French Pediatric Rare Tumor group (Fracture group), Institut Curie, 26, rue d'Ulm, 75005, Paris, France.

Purpose: The aim of this study was to retrospectively study survival and long-term morbidities of children with nasopharyngeal carcinoma (NPC) treated by induction chemotherapy and concurrent chemoradiation (CRT). The total dose of radiation was adapted to the response following neoadjuvant chemotherapy.

Methods: Children with non-metastatic NPC treated in France between 1999 and 2015 were retrospectively included in the study. The strategy combined neoadjuvant platinum-based chemotherapy, followed by adapted CRT to tumor response.

Results: In total, 95 patients (median age 15 years [range, 7-23 years], male-to-female ratio 1.8) with undifferentiated NPC were included; 59% of patients had TNM stage IV. Intensity-modulated radiotherapy (IMRT) was delivered to 57 patients (60%), while the other patients were treated with conformal RT (3D-RT). After a median follow-up of 4.5 years [range, 3.6-5.5 years], 13 relapses and seven deaths had occurred. The 3‑year overall and relapse-free survival (RFS) were 94% [95% CI, 85-97%] and 86% [77-92%], respectively. The locoregional failure rate was 6% [95% CI, 2-14]. Long-term treatment-related sequelae of grade 2+ were reported by 37 (50%) patients; odynophagia was significantly reduced treated by IMRT vs. conventional 3D-RT (7% vs. 55%, p = 0.015). Using a reduction dose of 59.4 Gy, 54 Gy, and 45 Gy, respectively, to the primary, involved, and uninvolved neck nodes, after a favorable tumor response, was not associated with an increased locoregional failure rate.

Conclusions: The survival rates for NPC have been considerably improved by means of multimodal therapy, but long-term locoregional morbidity remains common. Use of IMRT may induce less residual odynophagia. Radiation dose reduction adapted to chemotherapy response does not have a negative impact on outcome. These findings support the use of an RT protocol adapted to the tumor response to neoadjuvant chemotherapy for a long-lasting improvement in the patient's quality of life.
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http://dx.doi.org/10.1007/s00066-019-01461-6DOI Listing
June 2019

Management of vertebral radiotherapy dose in paediatric patients with cancer: consensus recommendations from the SIOPE radiotherapy working group.

Lancet Oncol 2019 03;20(3):e155-e166

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, Netherlands; Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands.

Inhomogeneities in radiotherapy dose distributions covering the vertebrae in children can produce long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia. In the published literature, many often interrelated variables have been reported to affect the extent of potential radiotherapy damage to the spine. Articles published in the 2D and 3D radiotherapy era instructed radiation oncologists to avoid dose inhomogeneity over growing vertebrae. However, in the present era of highly conformal radiotherapy, steep dose gradients over at-risk structures can be generated and thus less harm is caused to patients. In this report, paediatric radiation oncologists from leading centres in 11 European countries have produced recommendations on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimise the risk of long-term spinal problems. Based on available information, it is advised that homogeneous vertebral radiotherapy doses should be delivered in children who have not yet finished the pubertal growth spurt. If dose fall-off within vertebrae cannot be avoided, acceptable dose gradients for different age groups are detailed here. Vertebral delineation should include all primary ossification centres and growth plates, and therefore include at least the vertebral body and arch. For partial spinal radiotherapy, the number of irradiated vertebrae should be restricted as much as achievable, particularly at the thoracic level in young children (<6 years old). There is a need for multicentre research on vertebral radiotherapy dose distributions for children, but until more valid data become available, these recommendations can provide a basis for daily practice for radiation oncologists who have patients that require vertebral radiotherapy.
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http://dx.doi.org/10.1016/S1470-2045(19)30034-8DOI Listing
March 2019

Re-irradiation of locally recurrent pediatric intracranial ependymoma: Experience of the French society of children's cancer.

Radiother Oncol 2019 03 20;132:1-7. Epub 2018 Dec 20.

Oncology Radiotherapy Institut de Cancérologie de Lorraine, Vandoeuvre les Nancy, France.

Purpose: This study aimed to evaluate retrospectively the clinical results of re-irradiation for children with a locally recurrent brain ependymoma.

Methods: 33 full-dose re-irradiations were delivered to 31 children with a recurrent brain ependymoma after a standard treatment. Each child was followed up with clinical and MRI examinations. We evaluated overall survival, local recurrence free-survival and short term toxicity according to CTCAE 4.0 scale.

Results: With a median follow-up of 37 months (range, 0 to 107), median local recurrence free-survival was 31 months (range, 2 to 63) and median overall survival was 34 months (range, 3 to 63). It was significantly higher in patients who underwent surgery first, compared with re-irradiation only. Cumulated dosimetric data were available for 22 patients. On average, maximal BED to brain stem was 106,2 Gy (±35,4) for infratentorial re-irradiation. No acute toxicity grade >2 was reported and 1 case of brain radionecrosis treated successfully with steroids was reported after radiosurgery.

Conclusion: Local recurrence of brain ependymoma can be treated with full-dose re-irradiation, which can be hypofractionated with an acceptable short term toxicity in spite of high total doses delivered to OARs, especially brain stem.
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http://dx.doi.org/10.1016/j.radonc.2018.11.009DOI Listing
March 2019

Efficacy and toxicity of proton with photon radiation for locally advanced nasopharyngeal carcinoma.

Acta Oncol 2019 04 22;58(4):472-474. Epub 2019 Jan 22.

a Department of Radiation Therapy , Proton Therapy Center, Curie Institute , Orsay , France.

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http://dx.doi.org/10.1080/0284186X.2018.1543948DOI Listing
April 2019

The role of irradiated heart and left ventricular volumes in heart failure occurrence after childhood cancer.

Eur J Heart Fail 2019 04 27;21(4):509-518. Epub 2018 Dec 27.

CESP, Université Paris-Saclay, Villejuif, France.

Background: Paediatric cancer survivors have a high risk of developing cardiac diseases, and the most frequent cardiac disease is heart failure (HF). The radiation dose-volume effects in the heart and cardiac substructures have not been explored in childhood cancer survivors (CCS). Therefore, the role of irradiated heart volume in the occurrence of HF among this population remains unclear. The aims of this study were to determine the doses and irradiated volumes of the heart and left ventricle (LV) related to the risk of HF in CCS and to investigate the impact of anthracycline exposure on this risk.

Methods And Results: A case-control study nested in the French Childhood Cancer Survivors Study cohort. The mean heart and left ventricular doses and volumes indicators were estimated by reconstruction of individual treatments. A total of 239 HF cases and 1042 matched controls were included. The median age of HF diagnosis was 25.1 years. The median volume of the heart that received ≥ 30 Gy was 61.1% for cases and 16.9% for controls. In patients who did not receive anthracycline, the risk of HF was increased 3.6-fold when less than 10% of the LV received ≥ 30 Gy when compared to patients who were not exposed to any cardiac radiation and anthracycline.

Conclusions: Small irradiated volumes of the heart or LV were significantly associated with HF risk. To the author's knowledge, this is the first study to report a dose-response relationship based on dose-volume indicators in CCS, which can be translated efficiently into current clinical practice.
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http://dx.doi.org/10.1002/ejhf.1376DOI Listing
April 2019

Ewing's Sarcoma of the Head and Neck: Margins are not just for surgeons.

Cancer Med 2018 12 17;7(12):5879-5888. Epub 2018 Nov 17.

Department of Oncology for Child and Adolescents, Gustave Roussy, Villejuif, France.

Background, Methods: To describe the characteristics, treatments (systemic/local), and outcome (oncological/functional) of French patients with head and neck Ewing's sarcomas (HNES) registered in the Euro-Ewing 99 (EE99) database. Specific patient-level data were reviewed retrospective.

Results: Forty-seven HNES patients in the EE99 database had a median age of 11 years, 89% had bone tumors (skull 55%, mandible 21%, maxilla 11%), 89% had small tumors (<200 mL), and they were rarely metastatic (9%). Local treatment was surgery radiotherapy (55%), exclusively surgery (28%), or radiotherapy (17%). Metastatic relapses occurred in five patients with high relapse risk factors (metastasis at diagnosis, poor histological response, large tumors). Local progression/relapses (LR) after exclusive radiotherapy occurred in three patients with persistent extra-osseous residue and in four patients considered R0 margins (postchemotherapy surgery, without postoperative radiotherapy [PORT]), reclassified by pathological review as R1a. Pathological review reclassified 72% of R0 margins: 11/18 to R1a and 2/18 to R2. Five patients had confirmed R0 margins after postchemotherapy surgery without PORT and had no LR Eight patients had R2 margins (initial surgery without previous chemotherapy, with PORT) and had no LR With a median follow-up of 9.3 years, the 3-year LR rate, EFS, and OS were 84.8%, 78.6%, and 89.3%, respectively. Among the 5-year survivors, 88% had long-term sequelae.

Conclusion: To optimize HNES management, patients should be treated from diagnosis in expert centers with multidisciplinary committees to discuss treatment strategy (type of surgery, need for PORT) and validate surgical margins.
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http://dx.doi.org/10.1002/cam4.1801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308064PMC
December 2018

Tumor dissemination through surgical tracts in diffuse intrinsic pontine glioma.

J Neurosurg Pediatr 2018 Dec;22(6):678-683

3Department of Pediatric Hematology and Oncology.

OBJECTIVEDiffuse intrinsic pontine glioma (DIPG) is a highly aggressive and lethal brainstem tumor in children. In the 1980s, routine biopsy at presentation was abandoned since it was claimed "unnecessary" for diagnosis. In the last decade, however, several groups have reincorporated this procedure as standard of care or in the context of clinical trials. Expert neurosurgical teams report no mortality and acceptable morbidity, and no relevant complications have been previously described. The aim of this study was to review needle tract dissemination as a potential complication in DIPG.METHODSThe authors retrospectively analyzed the incidence of dissemination through surgical tracts in DIPG patients who underwent biopsy procedures at diagnosis in 3 dedicated centers. Clinical records and images as well as radiation dosimetry from diagnosis to relapse were reviewed.RESULTSFour patients (2 boys and 2 girls, age range 6-12 years) had surgical tract dissemination: in 3 cases in the needle tract and in 1 case in the Ommaya catheter tract. The median time from biopsy to identification of dissemination was 5 months (range 4-6 months). The median overall survival was 11 months (range 7-12 months). Disseminated lesions were in the marginal radiotherapy field (n = 2), out of the field (n = 1), and in the radiotherapy field (n = 1).CONCLUSIONSAlthough surgical tract dissemination in DIPG is a rare complication (associated with 2.4% of procedures in this study), it should be mentioned to patients and family when procedures involving a surgical tract are proposed. The inclusion of the needle tract in the radiotherapy field may have only limited benefit. Future studies are warranted to explore the benefit of larger radiotherapy fields in patients with DIPG.
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http://dx.doi.org/10.3171/2018.6.PEDS17658DOI Listing
December 2018

[Proton therapy in soft tissue and bone sarcomas].

Bull Cancer 2018 Sep 17;105(9):830-838. Epub 2018 Aug 17.

Lorraine cancer center, department of radiation oncology, 6, avenue de Bourgogne, 54519 Vandœuvre-lès-Nancy, France.

Sarcomas are a common type of tumor within the pediatric population. The utilization of proton therapy as a primary attribute the ability to spare adjacent healthy tissue, therefore, proton therapy has become a preferential indication in pediatrics compared to other photon irradiation modalities. Proton therapy is also a proven and historically validated irradiation technique in the treatment of chondrosarcomas and chordomas of the skull base and spine. Additionally, proton therapy can potentially limit irradiated healthy tissue volumes in adults and limit the risk of acute and late toxicities. The evaluation of the effectiveness of proton therapy in sarcomas is underway in many clinical situations in prospective trials, some of which are randomized.
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http://dx.doi.org/10.1016/j.bulcan.2018.05.008DOI Listing
September 2018

Pediatric Localized Intracranial Ependymomas: A Multicenter Analysis of the Société Française de lutte contre les Cancers de l'Enfant (SFCE) from 2000 to 2013.

Int J Radiat Oncol Biol Phys 2018 09 24;102(1):166-173. Epub 2018 May 24.

Department of Radiation Oncology, Institut Claudius Regaud, Institut Universitaire du, Cancer de Toulouse, Oncopole, Toulouse, France; Toulouse NeuroImaging Center, ToNIC, Université de Toulouse, Inserm, UPS, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France. Electronic address:

Purpose: The objective of this study was to analyze survival and prognostic factors for children, adolescents, and young adults treated with postoperative radiation therapy (RT) for intracranial ependymoma.

Methods And Materials: Between 2000 and 2013, 202 patients aged ≤25 years were treated in the 13 main French pediatric RT reference centers. Their medical records were reviewed for information, treatments received, and survival rates. All children had received postoperative RT- conformal, intensity modulated, or proton beam. In 2009, the prescribed standard dose in France rose from 54 Gy to 59.4 Gy.

Results: Median follow-up was 53.8 months (95% confidence interval [CI] 47-63.5). Median age at RT was 5 years (range 1-22), and 32% of the children treated were aged <3 years. Regarding treatment, 85.6% of patients underwent gross total resection, 62% of patients received conformal RT (vs 29% for intensity modulated RT and 8% for proton beam RT), 62.4% of patients received a dose >54 Gy, and 71% received chemotherapy. Of the 84 relapses, 75% were local. The cumulative incidence of local relapse was 24.4% (95% CI 18.2-31.2) at 3 years and 31.3% (95% CI 24-38.9) at 5 years. The 5-year disease-free survival (DFS) and overall survival rates were 50.4% (95% CI 42.2-58) and 71.4% (95% CI 63.1-78.2). Tumor grade was the only prognostic factor for local relapse and DFS. Tumor grade, age, and extent of resection were independent prognostic factors for overall survival.

Conclusions: We confirmed several clinical and tumoral prognostic factors in a large French multicenter study. DFS for intracranial ependymoma remains low, and new biological and imaging markers are needed to distinguish among different subtypes, adapt treatments, and improve survival.
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http://dx.doi.org/10.1016/j.ijrobp.2018.05.036DOI Listing
September 2018

Long term outcome of skull-base chondrosarcoma patients treated with high-dose proton therapy with or without conventional radiation therapy.

Radiother Oncol 2018 12 17;129(3):520-526. Epub 2018 Jul 17.

Institut Curie Protontherapy Center, Orsay, France; Department of Radiation Oncology, Hôpital Pitié-Salpêtrière-Charles-Foix, APHP, Paris, France.

Background And Purpose: Skull-base chondrosarcoma (ChSa) is a rare bone tumor and the outcome of patients with this malignancy has been documented only in a limited number of series with a restricted number of patients.

Objective: This study was conducted to assess the outcome and prognostic factors of a large cohort of ChSa patients treated with radiotherapy in two proton therapy centers.

Materials And Methods: From 1996 to 2015, 251 (male, 43.4%) patients (mean age, 42.0 ± 16.2 years) were treated with protons with (n = 135; 53.8%) or without photons (n = 116; 46.2%). Median delivered dose was 70.2 Gy. Failure-free survival (FFS), overall survival (OS) and CTCAE grade ≥3 toxicity free survival (TFS) were calculated using the Kaplan-Meier method.

Results: After a median follow-up of 88.0 months for surviving patients, local and distant failures were observed in 12 (4.8%) and 4 (1.6%) patients, respectively. Late failures >6 years were observed in 4 (33.3%) patients. The estimated 7-year FFS was 93.1%. Twenty-five (10%) patients died. The estimated 7-year OS was 93.6%. Tumor volume (p = 0.006) and optic pathway compression (p = 0.027) were significantly associated with the risk of treatment failure on univariate analysis. Treatment failure was significantly associated with a higher risk of death (hazard ratio = 126). The estimated 7-year TFS was 84.2%.

Conclusions: The outcome of skull-base ChSa patients treated with high-dose protons with or without photons is excellent, particularly for patients with small tumors with no optic pathway compression. Treatment failure was however associated with a significantly increased risk of death.
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http://dx.doi.org/10.1016/j.radonc.2018.06.040DOI Listing
December 2018

[Desmoplastic small round cell tumor in children, adolescents and young adults].

Bull Cancer 2018 May 22;105(5):523-536. Epub 2018 Mar 22.

Centre intégré de soins et de recherche en oncologie de l'enfant, adolescent et jeune adulte (SIREDO), université PSL, institut Curie, 75005 Paris, France. Electronic address:

Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma that typically affects pediatric and young adult patients with a median age in the general and in the pediatric population of 24.6 years (range 4-58 years) and 15.0 years (range 0-21 years) respectively, with a strong male predominance. This tumor is characterized by a specific t(11;22)(p13;q12) that results in fusion of EWS and WT1 genes which can be demonstrated by RT-PCR or by FISH. DSRCT most frequently presents as an intra-abdominal primary mass associated with peritoneal seeding and a highly aggressive pattern of spread. Generally, all tumors showed the typical histologic findings of variably sized clusters of poly-phenotypic small, round, or spindled cells lying in a desmoplastic stroma. Treatment of this malignancy remains a challenge. The combination of polychemotherapy regimens and aggressive surgery followed by whole abdomen radiation therapy represents nowadays a classical protocol for DSRCT. The survival rate of DSRCT patients is still disappointing around 20 %. However, the survival of patients who had complete resection of the tumor appears better. Hopes are turning to targeted therapeutics against this simple genomic sarcoma. Authors summarize medical knowledge of this rare tumor.
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http://dx.doi.org/10.1016/j.bulcan.2018.01.014DOI Listing
May 2018

Imaging biomarkers of outcome after radiotherapy for pediatric ependymoma.

Radiother Oncol 2018 04 2;127(1):103-107. Epub 2018 Mar 2.

ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, France; Department of Radiation Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole, France.

Background And Purpose: Ependymoma is the third most common brain tumor in children. Radiation therapy (RT) is systematically administered after maximum surgical resection, utilizing recent advances in radiation delivery. Imaging can make a significant contribution to improving treatment outcome. This prompted us to look for significant preoperative and postoperative imaging markers for survival.

Material And Methods: We undertook a national retrospective review of 121 patients who had undergone resection followed by RT. Preoperative tumor volumes on T1 and FLAIR images were delineated, together with postoperative hyperintense volumes on FLAIR images. Overall survival (OS) and disease-free survival (DFS) analyses included clinical data and volumes extracted from images.

Results: After a median follow-up of 38.5 months, 80.2% of patients were alive, but 39.7% had experienced at least one event. Statistically significant differences between patients with and without postoperative FLAIR abnormalities were found for both DFS (71.9% vs. 40.3%; p = 0.006) and OS (93.7% vs. 72.4%; p = 0.023) in the univariate analyses, and for OS (p = 0.049) in the multivariate analyses.

Conclusions: Postoperative FLAIR hyperintensities are a negative prognostic factor for intracranial ependymoma and may be a surrogate for residual disease. They could therefore prove helpful in patients' surgical and radiotherapeutic management.
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http://dx.doi.org/10.1016/j.radonc.2018.02.008DOI Listing
April 2018

Hippocampal Sparing During Craniospinal Irradiation: What Did We Learn About the Incidence of Perihippocampus Metastases?

Int J Radiat Oncol Biol Phys 2018 03 21;100(4):980-986. Epub 2017 Dec 21.

Centre Hospitalier Universitaire Lenval, Nice, France.

Purpose: To identify the incidence of patients with perihippocampal metastases to assess the risk of brain relapse when sparing the hippocampal area. Medulloblastoma (MB) represents 20% of pediatric brain tumors. For high-risk MB patients, the 3- to 5-year event-free survival rate has recently improved from 50% to >76%. Many survivors, however, experience neurocognitive side effects. Several retrospective studies of patients receiving whole brain irradiation (WBI) have suggested a relationship between the radiation dose to the hippocampus and neurocognitive decline. The hippocampal avoidance-WBI (HA-WBI) approach could partially reduce neurocognitive impairment in children treated for high-risk MB.

Methods And Materials: From 2008 to 2011, 51 patients with high-risk MB were treated according to the French trial primitive neuroectodermal tumor HR+5. Hippocampal contouring was manually generated on 3-dimensional magnetic resonance images according to the Radiation Therapy Oncology Group 0933 atlas. The distribution of metastases was assessed relative to the hippocampus: 0 to 5 mm for the first perihippocampal area and 5 to 15 mm for the rest of the perihippocampal area.

Results: The median patient age was 8.79 years (33% female). After a follow-up of 2.4 years, 43 patients were alive; 28 had had brain metastasis at diagnosis and 2 at relapse, with 16% in the first perihippocampal area and 43% in the rest of the perihippocampal area. Of the 18 patients without brain metastases at diagnosis, including M1 patients, none developed secondary lesions within the first or the rest of the perihippocampal area, after receiving 36 Gy. No clinical or biological factor was significantly associated with the development of perihippocampal metastases.

Conclusions: Our results suggest the HA-WBI strategy should be evaluated for the subgroup of high-risk MB patients without metastatic disease.
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http://dx.doi.org/10.1016/j.ijrobp.2017.12.265DOI Listing
March 2018

Pediatric Chordomas: Results of a Multicentric Study of 40 Children and Proposal for a Histopathological Prognostic Grading System and New Therapeutic Strategies.

J Neuropathol Exp Neurol 2018 03;77(3):207-215

Department of Neuropathology, Sainte-Anne Hospital, Paris, France.

Pediatric chordomas are rare malignant neoplasms, and few data are available for optimizing therapeutic strategies and outcome. This study aimed at evaluating how best to manage them and to identify prognostic factors. This multicentric retrospective study included 40 children diagnosed with chordomas between 1966 and 2012. Clinical, radiological, and histopathological data, treatment modalities, and outcomes were reviewed. The median age was 12 years old. Most chordomas were histologically classical forms (45.5%) and were mostly located at the skull base (72.5%). The overall survival (OS) was 66.6% and 58.6%, and progression-free survival (PFS) was 55.7% and 52% at 5 and 10 years, respectively. Total resection was correlated with a better outcome (p = 0.04 for OS and PFS, log-rank). A histopathological/immunohistochemical grading system recently crafted for adults was applied. In a multivariate analysis, it significantly correlated with outcome (PFS and OS, p = 0.004), and the loss of BAF47 immunoexpression appeared to be a significant independent prognostic factor (PFS, p = 0.033). We also identified clinical and histopathological parameters that correlated with prognosis. A new grading system combined with the quality of surgical resection could help classify patients to postpone radiotherapy in case of low risk. Targeted therapy and reirradiation at recurrence may be considered as potential therapeutic strategies.
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http://dx.doi.org/10.1093/jnen/nlx118DOI Listing
March 2018