Randomized phase III trial of metabolic imaging-guided dose escalation of radio-chemotherapy in patients with newly diagnosed glioblastoma (SPECTRO GLIO trial).

BACKGROUND: Glioblastoma (GBM) systematically recurs after a standard 60 Gy radio-chemotherapy regimen. Since magnetic resonance spectroscopic imaging (MRSI) has been shown to predict the site of relapse, we analyzed the effect of MRSI-guided dose escalation on overall survival (OS) of patients with newly diagnosed GBM. METHODS: In this multicentric prospective phase III trial, patients who had undergone biopsy or surgery for a GBM were randomly assigned to a standard dose (SD) of 60 Gy or a high dose (HD) of 60 Gy with an additional simultaneous integrated boost totaling 72 Gy to MRSI metabolic abnormalities, the tumor bed and residual contrast enhancements. Temozolomide was administered concomitantly and maintained for 6 months thereafter. RESULTS: One hundred and eighty patients were included in the study between March 2011 and March 2018. After a median follow-up of 43.9 months (95% CI [42.5; 45.5]), median OS was 22.6 months (95% CI [18.9; 25.4]) versus 22.2 months (95% CI [18.3; 27.8]) for HD, and median progression-free survival was 8.6 (95% CI [6.8; 10.8]) versus 7.8 months (95% CI [6.3; 8.6]), in SD versus HD, respectively. No increase in toxicity rate was observed in the study arm. The pseudoprogression rate was similar across the SD (14.4%) and HD (16.7%) groups. For O(6)-methylguanine-DNA methyltransferase (MGMT) methylated patients, the median OS was 38 months (95% CI [23.2; NR]) for HD patients versus 28.5 months (95% CI [21.1; 35.7]) for SD patients. CONCLUSION: The additional MRSI-guided irradiation dose totaling 72 Gy was well tolerated but did not improve OS in newly diagnosed GBM. TRIAL REGISTRATION: NCT01507506; registration date: December 20, 2011. https://clinicaltrials.gov/ct2/show/NCT01507506?cond=NCT01507506&rank=1.

[National meetings for complex cases in pediatric radiation oncology: Back on six years experience]. / Réunions nationales de cas complexes en radiothérapie pédiatrique : retour sur six années d'expérience.

INTRODUCTION: Pediatric cancers are rare, representing almost 2,500 new cases each year in France meaning 1% of all cancers. Since 2012, a twice-monthly national web-based conference was held in France. Any patient with a pediatric type cancer requiring radiotherapy can be discussed. It aims at answering the physician with specific radiation therapy questions on rare and complex indications, at promoting the use of referential and the inclusion into clinical protocols. RESULTS: From 2012 to 2018, 1,078 cases were discussed for 940 patients in 142 meetings. Mean age was 10 years old (4 months to 45 years). The mean number of attendants was 6 (2 to 32). We review in this paper the main clinical features discussed in the web-conference and the decision of the web-conference. In 85% cases, the first treatment proposed was mostly accepted, but in 15%, other proposals were done (modifications of target volumes, doses or indications). CONCLUSIONS: Between 2012 and 2018, more than 1,000 pediatric irradiation cases were discussed in our web-based conference leading to 15% of change in radiation protocol. The rarity and the complexity of these situations need those meetings. They provide a place to improve the global knowledge and the quality of the treatments provided.

Therapy and prognostic significance of regional lymph node involvement in embryonal rhabdomyosarcoma: a report from the European paediatric Soft tissue sarcoma Study Group.

PURPOSE: Regional lymph node disease (N1) is a component of the risk-based treatment stratification in rhabdomyosarcoma (RMS). The purpose of this study was to determine the contribution of nodal disease to the prognosis of patients with non-metastatic embryonal RMS (ERMS) and analyse their outcome by treatment received. PATIENTS AND METHODS: Between 2005 and 2016, 1294 children with ERMS were enrolled in the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS 2005 protocol, 143 patients with N1. Treatment comprised 9 cycles of ifosfamide, vincristine and dactinomycin. Some patients also received doxorubicin and/or maintenance if enrolled in the randomised studies. Local treatment was planned after 4 cycles of chemotherapy and included surgery to remove macroscopic residual tumour and/or radiotherapy (primary tumour and involved nodes). RESULTS: N1 patients were older and presented with tumours of unfavourable size, invasiveness, site and resectability. Unlike alveolar RMS, nodal involvement was more frequent in the head and neck area and rare in extremity sites. The 5-year event-free and overall survival were 75.5% and 86.3% for patients with N0, and 65.2% and 70.7% for patients with N1, respectively. The nodal involvement and the result of surgery at diagnosis (Intergroup Rhabdomyosarcoma Study group) were independent prognostic factors on multivariate analysis. Considering only patients with N1 ERMS, we were not able to identify any treatment variables which correlated with the outcome. CONCLUSION: In the case of nodal involvement, patients with ERMS present different characteristics and a better outcome than alveolar RMS. Regional nodal involvement is an independent prognostic factor in ERMS, therefore it is appropriate to include this population in the high-risk category.

Hypofractionated stereotactic body radiation therapy (SBRT) in pediatric patients: preliminary toxicity results of a national prospective multicenter study.

OBJECTIVES: While hypofractionated stereotactic body radiotherapy (SBRT) has been largely adopted in the adult setting, its use remains limited in pediatric patients. This is due, among other factors, to fear of potential toxicities of hypofractionated regimens at a young age. In this context, we report the preliminary acute (<3 months from SBRT) and middle-term (3-24 months) toxicity results of a national prospective study investigating SBRT in pediatric patients. METHODS: Between 2013 and 2019, 61 patients were included. The first 40 patients (median age: 12 y, range: 3-20) who completed a 2-year-follow-up were included in the present analysis. SBRT was used for treating lung, brain or (para)spinal lesions, either as first irradiation (35%) or in the reirradiation setting (65%). RESULTS: Acute and middle-term grade ≥2 toxicities occurred in 12.5 and 7.5% of the patients, respectively. No grade ≥4 toxicities occurred. Almost all toxicities occurred in the reirradiation setting. CONCLUSION: SBRT showed a favorable safety profile in young patients treated for lung, brain, and (para)spinal lesions. ADVANCES IN KNOWLEDGE: SBRT appeared to be safe in pediatric patients treated for multiple oncology indications. These results support further evaluation of SBRT, which may have a role to play in this patient population in the future.

Pattern of relapse in pediatric localized extremity rhabdomyosarcomas correlated with locoregional therapies administered.

BACKGROUND: Treatment of extremity rhabdomyosarcomas (RMS) includes chemotherapy, surgery, and radiotherapy. Lymph node irradiation is recommended in the presence of regional node involvement at diagnosis. The aim of this study was to analyze the correlation between the pattern of relapse of non-metastatic extremity RMS and the initial therapies delivered. METHODS: All patients with localized extremity RMS prospectively treated in France in the MMT-95 and RMS-05 protocols were selected. Extent of disease and pattern of relapse were evaluated by clinical examination and imaging. RESULTS: We identified 59 patients with clinical characteristics corresponding to unfavorable prognostic factors. Twenty patients (34%) were considered to have lymph node involvement at diagnosis. Regional node biopsy was performed in 32 patients (54%) and modified the lymph node stage in 8 of the 59 patients (14%). Seventy-three percent of patients received radiotherapy. Fifty-two patients achieved first remission. Overall, 26 patients underwent complete tumor resection, 17 had R1 margins, and 5 were not operated due to early tumor progression. With a median follow-up of 82 months (range: 5-287), 18 relapses had occurred, at least locoregional in 12 cases. The 5­year local and nodal control rates were 73% (63-86%) and 86% (77-95%), respectively. Five-year progression-free and overall survival were 57% (95%CI [45-72%]) and 70% (95%CI [58-84%]), respectively. CONCLUSION: The main sites of extremity RMS relapse are locoregional. Nodal failures in non-irradiated fields are not uncommon. We recommend systematic biopsy of in-transit nodes, especially in alveolar RMS and/or RMS with regional positive nodes at diagnosis to ensure their negativity.

Management of sarcomas in children, adolescents and adults: Interactions in two different age groups under the umbrellas of GSF-GETO and SFCE, with the support of the NETSARC+ network.

Sarcomas are a rare heterogeneous group of malignant neoplasms that can arise in almost any anatomic site and any age. Close collaboration among adult and pediatric cancer specialists in the management of these tumors is of foremost importance. In this review, we present the current multidisciplinary organization in care of patients with sarcoma in France and we review the main advances made in the last decades in systemic and radiotherapy treatment in the main sarcoma types diagnosed in children, adolescents and young adults (AYA), thanks to the international collaboration.

Locoregional Control and Survival in Children, Adolescents, and Young Adults With Localized Head and Neck Alveolar Rhabdomyosarcoma-The French Experience.

INTRODUCTION: The head and neck (HN) are the most frequent sites of pediatric rhabdomyosarcoma (RMS). Alveolar RMS (ARMS) represents ~20% of all RMS cases and frequently spread to lymph nodes (LNs). The aim was to report locoregional control, event-free survival (EFS), and overall survival (OS), according to clinical and pathological features, LN staging, and treatment modalities. METHODS: The study included all patients prospectively enrolled in EpSSG RMS 2005 study under 21 years of age with localized HN ARMS and diagnosed between 2005 and 2016 in France. Medical data including imaging, surgical report, and radiation therapy planes were analyzed. RESULTS: Forty-eight patients (median age 6 years; range 4 months-21 years), corresponding to 30 parameningeal and 18 non-parameningeal ARMS, were included. There were 33 boys (69%). Tumor locations included the following: orbit (n = 7) among which four cases had bone erosion, paranasal sinuses and nasal cavity (n = 16), deep facial spaces (n = 10), nasolabial fold (n = 8), and other non-parameningeal HN sites (n = 7). A fusion transcript of PAX3-FOXO1 or PAX7-FOXO1 was expressed in 33 of the 45 cases (73%) with molecular analysis. At diagnosis, 10 patients had primary resection of the primary tumor (PRPT) (none with microscopic complete resection) and 9 had LN staging. After induction chemotherapy, 26 patients (54%) had secondary resection of the primary tumor (SRPT) and 13 patients (27%) had cervical LN dissection. A total of 43 patients (90%) were treated with radiation therapy.With a median follow-up of 7 years (range 2-13 years), 5-year OS and EFS were 78% (95% CI, 63-88%) and 66% (95% CI, 51-78%), respectively. We observed 16 events (10 deaths): 4 local, 4 regional, 1 local and regional, and 7 metastatic. In univariate analysis, OS was only superior for patients under 10 years of age (p = 0.002), while FOXO1-negative ARMS, SRPT for parameningeal ARMS, and LN surgery were associated with significantly better EFS. CONCLUSION: Our study confirms a better outcome for fusion-negative ARMS and ARMS in children under 10 years. Moreover, LN surgery and SRPT of parameningeal tumor may improve EFS of ARMS. Larger studies are needed to confirm our findings.

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.

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.

Late complications of radiosurgery for cerebral arteriovenous malformations: report of 5 cases of chronic encapsulated intracerebral hematomas and review of the literature.

BACKGROUND: Chronic encapsulated intracerebral hematomas (CEIHs) are a rare, late complication of radiosurgery for intracranial AVM. We present 5 cases treated mostly by surgical excision and review the literature. METHODS: Patients (age 39, 42, 36, 31, 62) presented with headache, paresthesia, hemiparesis or were asymptomatic. CEIHs presented 10 to 13 years (median 12 years) post radiosurgery. Three patients had demonstrated early radiation induced changes post radiosurgery. Angiographic cure, assessed with DSA, was present in all cases except 1 case with a small nidus remnant. MRI demonstrated mixed lesions with a solid enhancing part, organized hematoma and extensive surrounding edema while three cases had also a cystic component. RESULTS: Excision of the CEIHs with complete or partial removal of the capsule was performed in 4 patients and resulted in marked clinical improvement. One patient was managed conservatively with administration of steroids as surgery was judged excessively hazardous with eventual stabilization of his symptoms. CONCLUSIONS: CEIHs are rare, late complications of radiosurgery for cranial AVM. They may be asymptomatic or provoke symptoms and may be preceded by early radiation induced changes. Complete removal of CEIHS is an effective treatment. Because of the long latency period of CEIHs, patients who had radiosurgery for brain AVMs should be followed by MRI at least 10 years even after complete obliteration.

Feasibility of Dose Escalation in Patients With Intracranial Pediatric Ependymoma.

Background and purpose: 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. Material and methods: 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]). Results: In most cases, the proton treatment resulted in higher quality indices (p < 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 (p < 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. Conclusion: 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.

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

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 Gyα/ß3 (±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.

Agreement between clinicoradiological signs at diagnosis and radiohistological analysis after neoadjuvant chemotherapy of suspected Wilms tumor rupture: Consequences on therapeutic choices.

INTRODUCTION: According to SIOP criteria, every patient presenting with preoperative Wilms tumor (WT) rupture must receive abdominal radiotherapy. Neoadjuvant chemotherapy reduces tumor volume and is responsible for the development of peritumoral capsule formation, which can mask tumor rupture on histological analysis, while it was clinically or radiologically obvious at diagnosis. Yet, there are no protocol recommendations for this particular presentation. OBJECTIVES: Study the agreement between clinicoradiological signs and histological confirmation after neoadjuvant chemotherapy of suspected WT rupture and describe the therapeutic choices arising in consequence. METHODS: Descriptive retrospective study on a monocentric series of patients with WT between June 1991 and August 2017. RESULTS: Out of 71 patients, 28 presented with suspected tumor rupture. We observed good agreement between clinical and radiological signs of suspected rupture (κ coefficient: 0.67). However, we assessed poor agreement between these signs and histological conclusions after neoadjuvant chemotherapy (κ coefficient: 0.27). Only five patients with clinicoradiological signs were overtreated with radiotherapy while tumor rupture had been refuted after histological review. The notion of abdominal trauma and the presence of intraperitoneal effusion seemed to guide collegial decision to overtreat these patients. No statistical difference in survival between patients with and without suspicion of tumor rupture at diagnosis was observed. CONCLUSION: This study highlights the need for recommendations in case of discrepancy between radiological and histological signs of rupture at diagnosis and after neoadjuvant chemotherapy. A study with stronger statistical power is necessary to define criteria that would lead to optimization of treatment in this context.

Dose-painting multicenter phase III trial in newly diagnosed glioblastoma: the SPECTRO-GLIO trial comparing arm A standard radiochemotherapy to arm B radiochemotherapy with simultaneous integrated boost guided by MR spectroscopic imaging.

BACKGROUND: Glioblastoma, a high-grade glial infiltrating tumor, is the most frequent malignant brain tumor in adults and carries a dismal prognosis. External beam radiotherapy (EBRT) increases overall survival but this is still low due to local relapses, mostly occurring in the irradiation field. As the ratio of spectra of choline/N acetyl aspartate> 2 (CNR2) on MR spectroscopic imaging has been described as predictive for the site of local relapse, we hypothesized that dose escalation on these regions would increase local control and hence global survival. METHODS/DESIGN: In this multicenter prospective phase III trial for newly diagnosed glioblastoma, 220 patients having undergone biopsy or surgery are planned for randomization to two arms. Arm A is the Stupp protocol (EBRT 60 Gy on contrast enhancement + 2 cm margin with concomitant temozolomide (TMZ) and 6 months of TMZ maintenance); Arm B is the same treatment with an additional simultaneous integrated boost of intensity-modulated radiotherapy (IMRT) of 72Gy/2.4Gy delivered on the MR spectroscopic imaging metabolic volumes of CHO/NAA > 2 and contrast-enhancing lesions or resection cavity. Stratification is performed on surgical and MGMT status. DISCUSSION: This is a dose-painting trial, i.e. delivery of heterogeneous dose guided by metabolic imaging. The principal endpoint is overall survival. An online prospective quality control of volumes and dose is performed in the experimental arm. The study will yield a large amount of longitudinal multimodal MR imaging data including planning CT, radiotherapy dosimetry, MR spectroscopic, diffusion and perfusion imaging. TRIAL REGISTRATION: NCT01507506 , registration date December 20, 2011.

Clinical and histological features of second breast cancers following radiotherapy for childhood and young adult malignancy.

OBJECTIVE: The purpose of this study was to determine the characteristics of early second breast cancer (SBC) among survivors of childhood and young adult malignancy treated with irradiation. METHODS: We conducted a multicenter retrospective study of women who presented with breast cancer aged 50 years or younger in nine French centers. RESULTS: 121 patients and 141 SBC were analyzed (invasive = 130; non-invasive = 11). The mean age at first cancer diagnosis was 15 years and at initial SBC diagnosis was 38 years. Bilateral disease before the age of 51 years was diagnosed in 16% of the females. The majority of SBC were invasive carcinomas (92%). Among the invasive carcinomas, 39% had a histoprognostic score of III, 3.1% overexpressed HER2 and 29% were triple negative. The proportion of triple negative phenotype SBC was higher in patients older at first cancer diagnosis [RR = 1.2, 95% CI (1.1-1.3)]. 94% of triple negative SBCs developed in breast tissue which had received >20 Gy. CONCLUSION: We found a high proportion of aggressive SBC following thoracic radiotherapy in childhood or early adulthood. Advances in knowledge: SBC screening is recommended by scientific societies for these child/young-adulthood cancer survivors in the same way as the one for high risk women because of constitutional mutations. Our results support these recommendations, not only because of a similar cumulative risk, but also because of the aggressive histological characteristics.

Imaging biomarkers of outcome after radiotherapy for pediatric ependymoma.

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.

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

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.

Long-term follow-up after childhood cancer in France supported by the SFCE-force and weakness-current state, results of a questionnaire and perspectives.

OBJECTIVE: The survival rate of children treated for cancer is currently about 80% at 5 years and we estimate that about 50,000 adults in France have survived childhood cancer. In 2011, there was a call for projects relating to long-term follow-up (LTFU), which led to several studies being conducted. Five years later, we sent a questionnaire to present LTFU in France and describe its strengths and weaknesses and to establish appropriate steps that should be taken. METHODS: A questionnaire was sent by email to all the members of the French Society of Childhood Cancers in spring 2016. The study involved 44 centres/hospitals with a Paediatric Oncology Department. RESULTS: 54 answers were analysed, provided by 31/44 (70%) centres working together with the French Society of Childhood Cancers. Screening is the main objective of LTFU care (90%). The main difficulties that arose were: lack of sufficient time to devote to this activity (57%), difficulties contacting adult childhood cancer survivors (aCCSs) (26%), aCCSs who ultimately did not show up to the consultation (19%), cost (15%), and lack of organization (13%). Seven LTFU programmes were identified: two regional organizations (Rhône Alpes and Grand Ouest), four centre-size organizations, and one national study (involving 15 Haematology Centres) relating to Child and Adolescent Leukaemia. CONCLUSION: LTFU is a major concern for French centres specialized in paediatric oncology. Organization is not well defined and difficulties still arise (Who are the best care providers? What frequency of care is most appropriate? etc.). Advances in knowledge: LTFU focused on health problems (physical, psychological, social, economic issues) that affect CCSs is needed to ensure that these patients regain the most optimal physical and emotional health possible. Practitioners suggest different ways to improve LTFU, such as national co-operation with Epidemiology Registers to promote homogenous LTFU care.

Intensity-modulated radiation therapy from 70Gy to 80Gy in prostate cancer: six- year outcomes and predictors of late toxicity.

OBJECTIVE: To report grade ≥2 overall late rectal and urinary toxicities in patients (pts) with prostate cancer treated by intensity-modulated radiotherapy (IMRT) at 3 dose-levels. Identify predictors of radiation toxicity and report biochemical progression free survival (bPFS). METHODS: A total of 277 pts were treated with 70Gy (10.8%), 74Gy (63.9%) and 80 Gy (25.3%) using IMRT without pelvic irradiation were analyzed. Short or long-course androgen deprivation therapy (ADT) was allowed in 46.1% of pts. The toxicity was described using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 scale. Cox regression models addressed demographics, disease and dosimetry characteristics as potential predictors of late grade ≥2 toxicity after adjusting for other modifying factors. RESULTS: The median follow-up was 77 months (range 15; 150). There was no grade ≥4 toxicity. The 5-year cumulative rate of grade ≥2 late rectal and urinary toxicities was 6.3% (95% CI = 3.8%; 10.3%) and 25.3% (95% CI = 19.8%; 31.8%) respectively. In multivariate analysis, only the dose (80Gy vs 74 and 70Gy) was found to increase the risk of rectal toxicity (HR = 2.96 [1.07; 8.20]). For pts receiving 74 Gy, International Prostate Symptom Score (IPSS) at baseline ≥8 (HR = 2.40 [1.08; 5.35]) and dose ≥73Gy delivered in more than 2% of bladder (D2%) were found to be predictors of bladder toxicity (HR = 3.29 [1.36; 7.98]). The 5-year biochemical relapse free survival was 81.0% [74.5%; 86.0%] in the entire population, 97.5% [83.5%; 99.6%] in the low risk group, 84.9% [76.7%; 90.3%] in the intermediate risk group and 66.4% [51.8%; 77.4%] in the high-risk group. D'Amico low (HR = 0.09 [0.01; 0.69]) and intermediate risk groups (HR = 0.50 [0.28; 0.88]) as well as PSA nadir ≥0.2 ng/ml (HR = 1.79 [1.01; 3.21]) were predictive of biochemical relapse. CONCLUSIONS: The rate of late rectal toxicity increased with higher doses, while Dmax ≥74Gy, D2% ≥ 73Gy for bladder wall and baseline IPSS ≥8 increased late urinary toxicity.

A French national breast and thyroid cancer screening programme for survivors of childhood, adolescent and young adult (CAYA) cancers - DeNaCaPST programme.

BACKGROUND: Survival of childhood, adolescent and young adult (CAYA) cancers has increased with progress in the management of the treatments and has reached more than 80% at 5 years. Nevertheless, these survivors are at great risk of second cancers and non-malignant co-morbidities in later life. DeNaCaPST is a non-interventional study whose aim is to organize a national screening for thyroid cancer and breast cancer in survivors of CAYA cancers. It will study the compliance with international recommendations, with the aim, regarding a breast screening programme, of offering for every woman living in France, at equal risk, an equal screening. METHOD: DeNaCaPST trial is coordinated by the INSERM 1018 unit in cooperation with the LEA (French Childhood Cancer Survivor Study for Leukaemia) study's coordinators, the long term follow up committee and the paediatric radiation committee of the SFCE (French Society of Childhood Cancers). A total of 35 centres spread across metropolitan France and la Reunion will participate. FCCSS (French Childhood Cancer Survivor Study), LEA and central registry will be interrogated to identify eligible patients. To participate, centers agreed to perform a complete "long-term follow-up consultations" according to good clinical practice and the guidelines of the SFCE (French Society of Children Cancers). DISCUSSION: As survival has greatly improved in childhood cancers, detection of therapy-related malignancies has become a priority even if new radiation techniques will lead to better protection for organs at risk. International guidelines have been put in place because of the evidence for increased lifetime risk of breast and thyroid cancer. DeNaCaPST is based on these international recommendations but it is important to recognize that they are based on expert consensus opinion and are supported by neither nonrandomized observational studies nor prospective randomized trials in this specific population. Over-diagnosis is a phenomenon inherent in any screening program and therefore such programs must be evaluated.