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The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have simultaneously developed with success treatment strategies with specific attention paid to long-term sequelae. Neurological sequelae may be reduced by establishing a diagnosis with an endoscopic biopsy and/or cerebrospinal fluid (CSF) and/or serum analysis, deferring the need to perform a radical surgery. Depending on markers and/or histological characteristics, patients are treated as either germinoma or non-germinomatous germ cell tumors (NGGCT). Metastatic disease is defined by a positive CSF cytology and/or distant drops in craniospinal MRI. The combination of surgery and/or chemotherapy and radiation therapy is tailored according to grouping and staging. With more than 90% 5-year event-free survival (EFS), localized germinomas can be managed without aggressive surgery, and benefit from chemotherapy followed by whole ventricular irradiation with local boost. Bifocal germinomas are treated as non-metastatic entities. Metastatic germinomas may be cured with craniospinal irradiation. With a 5-year EFS over 70%, NGGCT benefit from chemotherapy followed by delayed surgery in case of residual disease, and some form of radiotherapy. Future strategies will aim at decreasing long-term side effects while preserving high cure rates.

Inclusion of brain tumour patients in oncological protocols may be hampered by their neurological impairment. The goal of this study was to assess the reliability of Karnofsky Performance Scale (KPS) and WHO Performance Scale (WHO-PS) scores in this population. A cross-sectional survey was conducted through the Association des Neuro-Oncologues d‘Expression Francaise (ANOCEF) and European Neuro-Oncology Association (EANO) networks. Clinicians were asked to write a text defining their operative definition of a patient with ≥ 70 KPS and to assess KPS and WHO-PS in six different clinical case vignettes. Two hundred seventy-six clinicians sent a response. The operative definition mentioned a normal life (89%), what patients were able (26%) or unable (29%) to do, normal cognitive processing (8%) and caregivers (6%). Older physicians mentioned more often what patients were unable to do (p = 0.005). The two scales were homogeneous in less severely handicapped patients only. More patients were excluded for hemiplegia than for expressive aphasia. Older physicians significantly excluded more patients for KPS and WHO-PS. Speciality of the physician significantly influenced scoring. On multivariable analysis, age and speciality of the physicians were correlated with KPS and WHO-PS rating even if adjusted on cases. Discordant scoring increased with severity of the deficit: in nearly all cases, the KPS would have denied, while WHO-PS would have allowed, access to a trial. Performance scores assigned to brain tumour patients are clinician and score dependant. WHO-PS would allow more access to a trial. Specific criteria should be developed for patients with neurological deficits to facilitate their access to trials.

BACKGROUND MBL is the most common malignant pediatric brain tumor but represents 1% of adult brain tumors. Recent molecular classification suggests that MBL is not the same disease in children and adults. For standard risk pediatric medulloblastomas current therapy includes CSI at reduced doses (23.4Gy) associated with chemotherapy. Most adult patients with similar risk factors still receive CSI at 36 Gy±chemotherapy (CT): in the adult series treated according to the HIT protocol (CSI 35.2 Gy + boost to 55.2 Gy to posterior fossa followed in most patients by maintenance CT with lomustine, vincristine and cisplatin) a 73% 5-year PFS was reported {Friedrich, Eur J Cancer 2013}, so far the best published data. Hence retrospective experience of 23.4 Gy together with CT for adult patients in some institutions is worthwhile reporting. MATERIAL AND METHODS We gathered M0 patients, aged over 18 years with medulloblastomas and no/minimal post-surgical residues/no biological negative factor, between 1996–2018 in Centre Léon Bérard of-Lyon and Fondazione IRCCS Istituto Nazionale dei Tumori-Milan. RESULTS Forty-four patients were included, median age 26 (18–48) years,20 females. Median follow-up 90 months(10–227). Thirty-six and 8 received 23.4Gy and 30Gy CSI, respectively, + posterior fossa/tumor bed boost and CT in all: pre-RT (carbo/VPx2 courses or 8 drugs-in-one day x 2 courses (13 patients)) and/or post-RT (carbo/VPx2 courses in 11 and 8 drugs-in-one day x 2 courses in 10; CDDP/VCR/CCNU x 8courses in other 22). The 5/10 year PFS and OS were respectively 80.9±6.5%/76.8±7.4% and 88.4±5.5%/73.1±8.5%. Median progression time was 44 months. Relapses (8) were local (4), local+CSF or spine or bone in one instance each and bone only in one. Among variable considered, higher CSI dose than 23.4 Gy, pre-RT CT did not influence PFS, while females had a trend to better PFES and OS (P=0.07). CONCLUSION These combined series present results comparable to - or even better than- those obtained after high CSI doses highlighting the need for treatment redefinition in adults.

BACKGROUND The skills of adult versus pediatric neuro-oncologists are not completely similar though additive. Because the tumors and their protocols are different and the tolerance and expected sequelae are specific. Multidisciplinary meetings including adult and pediatric neuro oncologists are warranted to share expertise. MATERIAL AND METHODS Since 2008, on behalf of ANOCEF, GO-AJA and SFCE societies, a weekly national web based conference was held in France. Any patient with the following criteria could be discussed: Adolescent and Young Adults aged between 15 and 25 years, and any adult with a pediatric type pathology, including medulloblastoma, germ cell tumors, embryonic tumors, ependymoma, pilocytic astrocytoma. RESULTS Number of cases discussed increased from 8 to 202/year, with a mean number of 3 cases (1 to 7) discussed at each meeting. In 2018, 36 meetings were held, with a mean of 8 participants (2 to 14) issued from various French centers. 168 cases were discussed in 2018. Mean age was 30 years old (7 to 67). 45% were discussed at diagnosis; The patients had mostly medulloblastomas (n=47), ependymomas (n=24), low (n=21) or high grade gliomas (n=11), pineal tumors (n=20), germ cell tumors (n=9) and embryonal tumors (n=6). The rate of inclusion in protocols was increased since the opening of this web conference, especially for the germ cell tumor GCT SIOP protocol that is opened without age restriction, and in RSMA standard risk or MEVITEM relapse adult medulloblastoma protocols. CONCLUSION Multidisciplinary Web conference for AYAs is feasible and fruitful. It shares knowledge and increases the inclusion rate in protocols. It should be developped further.

BACKGROUND Even if medulloblastoma is considered as a curable disease, recurrent medulloblastoma has a poor prognosis, independently of therapy used. Medulloblastoma is very rare in adults, unlike children, and therapeutic strategies at recurrence are lacking. Nevertheless, adult teams sometimes use as “compassionate” chemotherapy some regimens published in children, such as the MEMMAT metronomic combination. However, this treatment, targeting both endothelial and proliferating tumor cells, has to date not been studied in the adult population. MATERIAL AND METHODS We present the case of a 40-year-old man, suffering from a right cerebellar SHH mutated medulloblastoma initially diagnosed and treated in 2014 by craniospinal radiotherapy associated with 4 cycles of carboplatine-VP16 following complete resection. Since April 2016, date of first relapse, numerous successive recurrences occurred, initially focal, treated by several surgeries (April and November 2016, January 2017), chemotherapy (rechallenge by carboplatine-VP16) then stereotactic radiotherapy. He then developed in October 2017 a new relapse in the posterior fossa, also associated with a meningeal dissemination on lumbar MRI. IK was 90%. He was then treated by TOTEM regimen (Temozolomide-Topotecan) followed by “Packer” regimen (Cisplatin-Belustine-Vincristin), without tumor control. However, because patient was non symptomatic with a KPS of 80%, we decided, according to the AJA French group, to propose what we presumed to be a “compassionate” chemotherapy, by metronomic pediatric regimen “MEMMAT”. For “supportive care” reasons, we decided not to realize the “Intrathecal part” of this regimen and administered to the patient intravenous bevacizumab (10 mg/kg d1-d14-d21), thalidomide (100 mg/d), celecoxib (300 mg bid), fenofibrate (160 mg/d) and etoposide (100 mg/d d1-21), alternating with cyclophosphamide (100 mg/d d22-42). RESULTS Clinical tolerance was very good, except grade 1 heel pain and fatigue; hematological toxicity was mild (transient grade 3 neutropenia, grade 4 lymphopenia); renal impairment, already present at the beginning, was increasing, and justified dose adjustment after 5 cycles and nephrologic explorations, ongoing. Radiological evaluation showed a complete radiological response with complete disappearance of enhancing lesions on first MRIs realized after 3 months (2 cycles); this response was confirmed after 6 months (4 cycles) and 9 months (6 cycles) on both cerebral and spinal MRI. Patient is now receiving the 7th cycle. CONCLUSION We report here the first case of a complete and sustaining response of an adult multi-recurrent metastatic medulloblastoma treated by a pediatric antiangiogenic metronomic regimen “MEMMAT”. This promising result incites to develop a dedicated prospective trial in adults in view to confirm the interest of this strategy.

BACKGROUND Optimal strategy for treatment of relapsing intracranial malignant germ cell tumors remains ill-defined. Authors describe the French experience over a 25-year period. MATERIAL AND METHODS Relapsing patients were retrieved by their participation in the SFOP-TGM 90-92 or GCT 96 protocols or from National Childhood Solid Tumour Registry. RESULTS The cohort included Group A: documented germinomas (n=14), Group B: patients treated as germinomas without histopathological proof (n=5) and Group C: secreting germ cell tumours (n=25). Patients all received standard dose chemotherapy, and some high dose chemotherapy (VP16 Thiotepa with stem cell rescue) and/or various type of radiation. The 5 year EFS and OS post relapse are: 79%[47 to 93%] and 86% [54 to 96%] respectively in group A, 20% [1 to 58%] and 80% [20 to 97%] respectively in group B, 56% [35 to 73%] and 60% [38 to 76%] respectively in group C. Among 14 Group A patients, 7/12 receiving high dose versus 3/3 receiving standard dose chemotherapy, and 9/11 re-irradiated versus 1/3 not re-irradiated are CR2. Among 21 Group C patients. who had received radiation in first line, 10/15 receiving high dose versus 1/6 receiving standard dose chemotherapy, and 7/11 re-irradiated versus 4/10 not re-irradiated are CR2. CONCLUSION The outcome of relapsing germinoma is favourable and intensity of second line remains matter of debate. High dose chemotherapy with radiotherapy, when feasible, should remain the reference for treatment of a relapsed non germinoma, though more active treatments are warranted.

Resume Le cancer reste la premiere cause de deces par maladie chez l’enfant et l’adolescent. Donner un large acces aux innovations therapeutiques est un objectif strategique majeur de l’onco-hematologie pediatrique en Europe. Objectif Analyser la participation des enfants et adolescents aux essais precoces de nouveaux medicaments anticancereux en France. Methode Les donnees saisies des essais precoces ouverts aux inclusions dans les centres de la SFCE de 2010 a 2013 ont ete exploitees. Resultats Trente-sept essais precoces ont inclus 607 patients (487 porteurs d’une tumeur solide [80 %], 120 d’une leucemie ou d’un lymphome [20 %]). Il s’agissait de 15 essais de phase 1, 5 de phase 1/2 et 17 de phase 2 evaluant 33 nouveaux medicaments (66 % de therapies ciblees) et une nouvelle formulation. Soixante-huit pour cent etaient des essais internationaux du reseau europeen ITCC. Soixante-deux pour cent etaient promus par un industriel du medicament. En 2013, il y a eu 195 inclusions, soit +77 % par rapport a 2010, dans 30 essais ouverts. Les inclusions en France representent 50 % des inclusions dans le reseau europeen ITCC sur les 10 dernieres annees. Conclusion La France est attractive et leader en Europe. Il existe une dynamique de reseau qui est claire et efficace avec un nombre d’essais ouverts par an qui a triple en 4 ans et un nombre d’inclusions qui a presque double. Mais ceci reste insuffisant par rapport aux besoins medicaux et aux attentes des parents et des patients. L’objectif est de doubler les inclusions dans un essai precoce a l’issue du Plan Cancer 3.

Adult medulloblastomas are orphan diseases that differ from their pediatric counterpart. Most are classified as classic or desmoplastic and fall in the SHH subgroup, mainly with loss-of-function mutations in PTCH1 and some by TP53-mutation due to underlying germline mutation. Activation of the WNT pathway is sporadic, although underlying Turcot syndrome may be present. One-third of tumors are issued from group 4. Most adult studies are small non-randomized retrospective heterogeneous studies performed at a single center with short follow-up. Standard craniospinal irradiation followed by maintenance chemotherapy (CCNU, cisplatin-vincristine) results in a 4-year event-free survival (EFS) and overall survival (OS) of 68% and 89% respectively in standard-risk adults, and in a 4-year EFS and OS of 50% and 90%, respectively in high-risk adults. Several pooled analyses point out the potential role of chemotherapy in adults. The feasibility of pediatric protocols in adults is sometimes hampered because of blood and peripheral nerve toxicity. In the near future, subgroups of medulloblastomas may be treated by personalized therapies. With prolonged follow-up, adults fare worse. Long-term sequelae and second line treatment are not well defined in adults. Prospective studies are ongoing to define optimal first-line and relapse treatments.

Blurred vision is common among patients with brain tumor. It may result from increased intracranial pressure and/or compression and/or invasion of the optic pathway. We assessed the incidence and etiology of visual impairment in patients with intracranial germinoma tumors (ICGT). METHODS AND MATERIALS: We performed a blinded retrospective review of the charts and initial imaging of 28 patients with ICGT. Thirteen tumors were pineal; 5 were supraoptic, 7 bifocal; and one each involved the optic nerve, corpus callosum, and brainstem. RESULTS: Twelve patients reported decreased visual acuity. Six of them demonstrated no clinical or radiological signs of raised intracranial pressure; five showed invasion and/or compression of the anterior optic pathway. Two of those were initially managed as “retrobulbar neuritis” when endocrinological symptoms prompted magnetic resonance imaging. The involvement of the optic pathway was underestimated and both relapsed. Three further patients had supraoptic mass with contiguous involvement and/or compression of the chiasm. None of the patients with loss of visual acuity and headache and none of those with no loss of visual acuity had invasion/compression of the anterior optic pathway and none relapsed. CONCLUSIONS: Compression and/or invasion of the optic pathway by germinoma is not rare and should not be overlooked when thickening and/or contrast enhancement is detected. Radiotherapy fields should be extended accordingly.

BACKGROUND Personalized anti-tumoral therapies may currently be proposed on the basis of immuno-histochemistry, but also next-generation sequencing and comparative genomic hybridization. ProfiLER trial explored the feasibility, efficacy and the impact of molecular profiling for patients with solid or hematological advanced cancers including brain tumors. MATERIAL AND METHODS Patients with primary brain tumors, pre-treated with at least one line of anti-cancer treatment, could be included in this multicentric prospective trial. A molecular profile (next-generation sequencing and comparative genomic hydridization) was established on fresh or archived sample. Weekly molecular tumor board analysed results to propose as far as possible a molecular targeted therapy. RESULTS between February 2013 and December 2015, 141 patients with primary brain tumor were enrolled. One hundred five samples were further analyzed as 30 samples were excluded, and 6 are on-going. The rate of screen failure was 16/33 for stereotactic biopsy (49%) versus 11/104 (11%) for removal. The main representative histologic type of tumors were glioblastoma (n=46, 43,8%), low grade glioma (n=26, 24,8%), high grade glioma (n=12, 11,4%) and atypical and anaplastic meningioma (n=8, 7,6%). Median delay between the diagnostic of the primitive tumor and the inclusion in ProfiLER study was 2.7 years (0.2 - 29 years). Median delay between the consent and the results of the multidisciplinary meeting was 2.8 months (1–7.1 months). Forty-three patients (41%) presented at least one “druggable molecular alteration”. The most frequently altered genes were CDKN2A (n=18, 29%), EGFR (n=12, 20%), PDGFRa (n=8, 13%), PTEN (n=8, 13%), CDK4 (n=7, 11%), KIT (n=6, 10%), PIK3CA (n=5, 8%), MDM2 (n=3, 5%). Sixteen patients could not have a proposition of specific treatment due to death before MBT (n=5, 31.3%), lack of available clinical trials (n=9, 56%), or ambiguous results (n=2, 12.5%). Among the 27 patients (26%) for whom a specific therapy has been proposed, only six patients ultimately received a medical targeted therapy (everolimus n=3, erlotinib n=1, ruloxitinib n=1, sorafenib n=1). Four patients discontinued the treatment for toxicity, the 2 others for clinical progression. CONCLUSION routine high-throughput sequencing is feasible for brain tumors but delays should be reduced to be able to propose targeted therapies to patients fit enough to benefit from experimental treatment. Macroscopic surgery is the best way to obtain workable samples. Specific panel genes for neurologic tumors should be developed, as well as change of practices concerning exclusion criteria in clinical trials.

BACKGROUND Inclusion criteria for oncological protocols often use the Karnofsky performance score (KPS) >=70 or the WHO performance score (PS) 0–2 as a cut-off value. Inclusion of neuro-oncology patients may be hampered, when general condition is preserved, while performance is decreased due to physical handicap. The goal of this study is to compare the KPS and PS assessments according to the status of the clinician. MATERIAL AND METHODS A cross-sectional survey was conducted through ANOCEF and EANO networks. Clinicians evaluated KPS and PS in 6 clinical situations concerning neuro oncology patients (from youngest and fittest to oldest, crippled with comorbidities). RESULTS The rate of PS 2 increased significantly from case 1 to 6. Sex or nationality of the clinicians had no impact when adjusting on clinician characteristics. Conversely, speciality (residents/general practitioner vs neurosurgeons vs neurologists vs oncologists), impacted KPS or PS evaluations (p In a multivariate analysis, age and speciality were correlated with KPS and PS rating even if adjusted on cases. Discordant decision for protocol inclusion (i:e: (KPS) >=70 vs PS 0–2) showed little discrepancy in case 1 (2.3%), while discrepancy increased to respectively 16, 46, 39, 33 and 43% for cases 2 to 6: in nearly all cases, the KPS would have denied access to a trial, while WHO Ps would have allowed CONCLUSION Rating of KP and PS is subjective in neuro oncology patients: influenced by speciality, age and inclusion habit (for KPS) of clinicians, PS 0–2 allows usually more inclusion than KPS>=70 in more severely disabled patients. A Neuro oncology specific KPS and/or PS definition is warranted to allow more widely inclusion of patients with exclusive neurologic handicap.

BACKGROUND Choroid plexus tumours represent less than 1% of brain tumours. Low-grade papilloma may be treated with gross total surgical resection, while in disseminated progressive atypical choroid plexus papilloma (APP), there is no standard treatment: various chemotherapy regimens have been reported. Since this tumour is characterized by a rich vascular component, antiangiogenic therapy is an attractive treatment. The use of Bevacizumab has already been reported in three patients. Authors expand this experience with 5 further patients diagnosed with progressive APP treated with bevacizumab. MATERIAL AND METHODS Patients were recruited through the weekly Adolescent Young Adult French web conference. They have been treated with bevacizumab 10 mg/kg by intravenous injection each 2 to 3 weeks. Their clinical status and radiological response are reported: Karnofsky Index (KI), Pain Scale (PS) and RANO criteria were used. RESULTS All our patients had a progressive disease prior to bevacizumab. Pt 1: 41 years old; APP with cranio-spinal dissemination; Previous treatments: local and cranio-spinal irradiation in 2012 and in 2014; surgery: complete and partial resection in 2010, 2014, and VP shunt in 2018; Bevacizumab: total of 33 cures in 18 months. Result: radiological and clinical stabilization. Pt 2: 58 years old; APP with cranio-spinal dissemination; Previous treatments: surgery: VP shunt and gross total resection, in 2006; VP shunt, in 2011. Bevacizumab: total of 4 cures, in 2 months. Result: radiological and clinical stabilization. Pt 3: 34 years old; APP with cranio-spinal dissemination; Previous treatments: surgery: gross total resection, in 1992, and shunt in 2008. Bevacizumab: total of 21 cures, in 21 months. Result: radiological and clinical stabilization. Pt 4: 63 years old; APP with cranio-spinal dissemination; Previous treatments: surgery: surgical resection and VP shunt in 2013; chemotherapy: temozolomide. Bevacizumab: 29 months (still treated). Result: radiological and clinical stabilization. Pt 5: 62 years old; APP with cranio-spinal dissemination; Previous treatments: surgery: gross total resection in 1999 and VP shunt in 2009; chemotherapy: Carboplatin Vespesid. Bevacizumab: 23 cures, in 14 months. Result: radiological stabilization and clinical amelioration. CONCLUSION Despite their previous worsening disease, all patients obtained a stabilization or amelioration of their IK and PS under bevacizumab. Bevacizumab should be evaluated in a multicentric trial as standard therapy for disseminated metastasized progressive choroid plexus tumours.

BACKGROUND The brainstem is the second location of brain tumors after optic pathways in NF1. In NF1 children, brainstem gliomas are usually indolent and have a better prognosis than their counterparts in non NF1 children. In contrast, the natural history and prognosis of adult brainstem gliomas in NF1 are nearly unknown. MATERIAL AND METHODS We conducted a retrospective analysis of medical records and MRI of adult NF1 patients followed for a brainstem glioma in 8 centers over a 17 years period (2000–2017). Clinical and imaging characteristics, management and outcome were analyzed. RESULTS Twenty five patients were included in the study (13 males and 12 females) with a median age of 32 (range 17–58). The epicenter of the tumor was located into the pons n=13 (52%), the mesencephalon n=7 (28%), the medulla oblongata n=5 (20%). On MRI, contrast enhancement was seen in 19 tumors (76%). Pathological examination was available in 13 tumors (52%) and showed a high grade astrocytoma (III or IV) in 9 tumors. Five patients were asymptomatic, 3 remained asymptomatic during the follow-up (median follow-up: 86 months, range 22–124). Twenty patients were symptomatic with a median duration of symptom of 2.5 months (range 1–10) before diagnosis. Among these symptomatic patients, 15 died from tumor progression despite treatment with radiation therapy and or chemotherapy. The median overall survival of symptomatic patients was 36 months. CONCLUSION Brainstem gliomas are rare tumors in adults with NF1. Unlike children, adult brainstem gliomas seem to have an unexpected poor prognosis, suggesting the disease may be different in adulthood.

Central nervous system (CNS) germ cell tumors (GCTs) are separated into germinomas and nongerminomatous germ cell tumors (NGGCTs). The latter group includes teratoma (mature and immature), teratoma with malignant transformation, yolk sac tumor, embryonal carcinoma, choriocarcinoma, and mixed GCTs. CNS GCTs can be classified based on their histologic appearance and immunohistochemical profiles with histologic subtype being the best predictor of outcome. Germinomas respond exceptionally well to chemotherapy and irradiation and have been shown to have survival rates in excess of 90 %. In contrast, NGGCTs are more resistant to therapy and require more intensive chemotherapy, as well as higher doses of irradiation. There is little information on the histogenesis and molecular genetics of CNS GCTs. Fluorescent in situ hybridization (FISH) studies have shown a gain of X chromosome in a majority of GCTs. Other studies have shown that 12p abnormalities (gains and isochromosome 12p) are common, especially in germinomas. Gene expression analysis studies show overexpression of self-renewing pluripotency genes and genes responsible for tumor growth and differentiation in various tumors with no significant differences in gene expression between CNS GCTs of similar histology arising at different sites and different ages within the pediatric age group. Differences in microRNA expression have been demonstrated between histologic subtypes of CNS GCTs, and their potential use as a biomarker in the serum and cerebrospinal fluid is being explored. KIT mutations are the most commonly found abnormality on whole genome sequencing, predominantly in germinomas, followed by genes involved in the MAPK signaling pathway, suggesting a role for KIT inhibitors in the management of these tumors.

Background To evaluate the efficacy of BCNU, cisplatin, and vincristine (BCV regimen) in a prospective nonrandomized study among newly diagnosed children with high-grade glioma. Procedure Following surgery, patients received a combination of BCNU + cisplatin + VP16 (BCV), over 3 consecutive days. Patients with residual tumor continued this regimen unless no further improvement was observed on MRI, for a maximum of six courses. Patients who underwent complete surgical resection received six courses of adjuvant BCV. Results Seventy-three patients were enrolled. Out of 66 eligible patients with central pathology review, the diagnosis of high-grade glioma was confirmed in 53 cases. The response rate was 20%. With a median follow-up of 128 months, 5- and 10-year event free survival rates are 16 ± 9 and 13.3 ± 9.4%. In univariate analysis, two prognostic factors were statistically significant: extent of resection and tumor location, while macroscopic total resection was the only significant prognostic factor in the multivariate analysis. The response to BCV did not translate into improved event free survival. Interstitial pneumonitis occurred in seven patients, leading to six deaths. Conclusion This BCV regimen could not be recommended in the treatment of high-grade gliomas in children, according to its lack of efficacy and its unacceptable pulmonary toxicity. Pediatr Blood Cancer 2007;49:803–807. © 2006 Wiley-Liss, Inc.

Aim Improvement of EFS of children older than 3 years with high risk medulloblastoma. Methods Between 1993 and 1999, 115 patients (3–18 years, mean 8 years) with high risk medulloblastoma were included. After surgery treatment consisted of chemotherapy (‘8in1’ and etoposide/carboplatin) before and after craniospinal radiotherapy. Results Patients were staged using Chang-criteria (PF residue only, M1 and M2/M3) by local investigator as well as by central review panel (82.4% concordance). Chemotherapy was well tolerated without major delays in radiotherapy. With a mean follow up of 81 months (9–119), 5-year EFS was 49.8% and OS 60.1%. In detail according to subgroups EFS was 68.8% for PF residue only, 58.8% for M1 disease and 43.1% for M2/M3. Conclusion M1 patients are legitimate high risk patients. Survival rates are still very low for high risk medulloblastoma patients and future trials should therefore focus on more intensive (chemotherapy/radiotherapy) treatment.

The aim of this study was to evaluate a chemotherapy strategy that avoids radiotherapy in first-line treatment of young children with high-grade glioma. A total of 21 children under 5 years of age received the BBSFOP protocol, comprising seven cycles of three drug pairs (carboplatin/procarbazine, cisplatin/etoposide and vincristine/cyclophosphamide) administered over a 16 month period. Radiotherapy was performed in case of recurrence/progression. Median age at diagnosis was 23 months. Histology was classified as World Health Organisation (WHO) grade III in 13 and grade IV in 8. Of the 13 children with a residual tumour, chemotherapy induced 2 partial responses (PR), 1 minor response (MR) and 1 stable disease (SD) with no recurrent disease. Five-year progression-free survival was 35% and 5-year overall survival was 59%, with a median follow-up of 5.2 years. At the last update, 12 children were alive (10 without radiotherapy). In conclusion, this study shows that an adjuvant chemotherapy first approach is safe and allows radiotherapy to be avoided in selected children.

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, 'DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m(-2) for Group A and 100 mg m(-2) for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.

La prise en charge des tumeurs cerebrales pediatriques vise a ameliorer les taux de survie, sans accepter des sequelles incompatibles avec une bonne qualite ulterieure de vie. Le modele du medulloblastome est exemplaire: apres exerese locale, la radiotherapie crâniospinale (± chimiotherapie) reste le standard chez l’enfant de plus de cinq ans au diagnostic. Elle est cependant pourvoyeuse de sequelles neuropsychologiques d’autant plus importantes que l’âge au diagnostic est faible. Aussi la chimiotherapie exclusive est-elle proposee en cas d’exerese complete avant l’âge de cinq ans avec des taux eleves de guerison. La prise en charge multidisciplinaire est abordee.

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children.

Retinoblastoma is the most common primary cancer of the eye in children. The prognosis for survival is excellent. The current therapy includes an improved survival rate and decreased iatrogenic sequelae. The relative risk of a second tumor in survivors of retinoblastoma is documented, especially in those who carry a germline RB mutation. It is strongly increased in case of radiation therapy. The most common types of second primary tumor are sarcoma of soft tissues and osteosarcoma. We present here a rare case of a retinoblastoma patient who received radiation therapy as a part of his treatment and developed a papillar thyroid cancer as a second malignancy. Papillar thyroid cancer has a good prognosis. Systematic screening for thyroid carcinoma should be undertaken in patients irradiated for congenital retinoblastoma.

The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420 mg/m2). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity. © 2001 Cancer Research Campaign http://www.bjcancer.com

Background In children over 1 year of age with metastatic neuroblastoma, clearance of metaiodobenzylguanidine (MIBG) skeletal uptake after four courses of induction chemotherapy is one of the most powerful prognostic factors. How subjective is quantification of MIBG uptake, and can earlier MIBG scintigraphy separate good and bad responders? Procedure The data from 47 patients who received uniform induction therapy were reviewed. A novel scoring system of MIBG update intensity was proposed. Initial, intermediate (after two courses), and final (after four courses) intensities were scored (0 to 21 points) independently by six different observers. The initial global score and the relative score (calculated by dividing the global score after two courses by the initial score) were compared to the final score. Good responders were those who scored 0 at final MIBG. Results Between two observers, the correlation coefficient for the global score was superior to 0.80, in nine of ten comparisons established between observers 1–5. The initial score did not predict the final score insofar as only nine of fourteen patients with low initial scores were good responders. The relative score also failed to predict outcome; only six of ten patients with favorable relative score (i.e.

Our objective was to adapt and validate the Health Utilities Index Mark 2 (HUI 2) and HUI 3 health status classification systems self-report questionnaire in a population of children with cancer, a group of 42 children already included in a multi-centre database designed by the Group on Brain Tumors in Children of the French Society for Pediatric Oncology. Children were recruited during a routine consultation. Most of them had completed treatment. The version of the questionnaire for French adults was adapted linguistically for children. Open-ended queries by children about the comprehensiveness of the questions and very low non-response rates showed a good acceptability of the questionnaire. The main psychometric properties of the HUI 2 and HUI 3 classification systems were assessed in 3 groups of raters (child, parent, physician): construct validity was tested against the rating of the child's health state on a Likert scale and through comparison with clinical data, and internal consistency was determined through multi-trait analysis. Weighted and unweighted kappa values were used to measure the inter-rater agreement between the child's, parent's and physician's assessment of the child's health state. The convergent validity was satisfactory, with better results when the physician's assessment was used. The most affected attributes were the expected ones (i.e., cognition, pain and emotion). Disagreement was observed between the 3 raters, more often in the same direction: taking the child's assessment as the reference, the parents tended to under-estimate the health status while physicians tended to over-estimate it.

PURPOSE The three-drug combination of melphalan (M), etoposide (E), and carboplatin (C) followed by autologous stem-cell (ASC) rescue has been evaluated prospectively by the French Society of Pediatric Oncology (SFOP) in pediatric high-risk recurrent (HRR) Wilms' tumor (WT) patients with chemotherapy-responsive disease. PATIENTS AND METHODS From October 1988 to October 1994, 29 patients with HRR WT were treated in nine SFOP centers. Two additional patients with stage IV anaplastic WT were consolidated in first complete response (CR) with the same regimen and have been studied separately. The regimen consisted of M 180 mg/m2 for 1 day, E 200 mg/m2/d for 5 days, and C at a daily targeted area under the concentration-time curve (AUC) of 4 mg x min/mL for 5 days. ASCs were reinfused 48 hours after M. RESULTS Twelve of 28 assessable patients with HRR WT are still in continuous CR at a median of 48.5 months (range, 36 to 96) after consolidation. Disease-free survival (DFS) and overall survival (OS) estimated by the Kaplan-Meier method at 3 years were 50%+/-17% and 60%+/-18%, respectively. Sixteen patients relapsed at a median of 8.5 months (range, 3 to 53) after consolidation. Toxicity data are available in 31 grafted patients. Grade III and IV toxicities included hematologic side effects (n=31), hemorrhage (n=8), mucositis (n=24), diarrhea (n=12), renal disorders (n=8), and pneumonitis (n=3). CONCLUSION The adverse prognostic factors (APF) used to select patients for this dose-intensive chemotherapy define children with very-poor-risk recurrent WT. Despite high treatment-related toxicity, about half of these patients remain disease-free at 3 years. Patient outcome is statistically better when high-dose chemotherapy (HDCT) is performed as early as the second CR or partial response (PR). Novel therapeutic approaches with innovative preparative regimens are warranted for the remaining high-risk patients.

PURPOSE The European Bone Marrow Transplantation (EBMT) Solid Tumor Registry (STR) contains detailed information on children with advanced neuroblastoma who, after standard-dose induction chemotherapy and surgery, received myeloablative megatherapy (MGT) followed by stem-cell transplantation (SCT). This data base was analyzed to identify factors that predict event-free survival (EFS). PATIENTS AND METHODS Eligibility criteria were stage IV neuroblastoma, age over 1 year at diagnosis, and no relapse before MGT/SCT. Between February 1978 and July 1992, 549 patients were registered by 36 European transplant centers. The median age at diagnosis was 36 months (range, 13 to 216 months) and the male-female ratio was 1:45. Before MGT, 157 patients were in complete remission (CR), 156 in very good partial remission (VGPR), and 208 in partial remission (PR), whereas 24 had had only a minor response (MR). One hundred ten of 546 patients had undergone two successive MGT procedures. The median observation time was 60 months (range, 12 to 187 months). RESULTS Actuarial EFS is 26% at 5 years. Multivariate analysis by the Cox proportional hazards regression model included 529 patients with complete data sets. After adjustment for treatment duration before MGT and double MGT procedures, two adverse, independent risk factors that influenced EFS were identified: (1) persisting skeletal lesions before MGT as defined by technetium (99TC) scans and/or meta-iodobenzylguanidine (mIBG) scans (P = .004) and (2) persisting bone marrow involvement before MGT (P = .03). CONCLUSION After induction treatment, persisting skeletal disease as defined above and persisting bone marrow involvement may be predictive of a particularly poor outcome. Physicians may consider this an additional important tool to decide the patient's management.

The fortuitous discovery of a left posterior cervico-mediastinal mass during hospitalization for hemolytic anemia in an 18 month old baby is reported. Metaiodobenzylguanidine (MIBG) uptake suggested a sympathetic tissue origin of the mass despite negative catecholamines excretion, but histopathologic examination revealed a juvenile capillary angioma within a normal sympathic ganglion.

Between March 1990 and December 1994, 316 consecutive children with localised neuroblastoma were registered in the French NBL 90 study. In addition to the assessment of a new chemotherapy regimen in unresectable neuroblastoma, we evaluated the prognostic significance of MYC N amplification and loss of the short arm of chromosome 1 (LOH1p). MYC N was found in 22/225 children (10%) and associated with unfavourable clinical features such as age at diagnosis > 1 year and large and unresectable tumours. LOH1p was observed in 9/91 patients (10%), of whom some had favourable prognostic factors such as age at diagnosis n = 4), INSS stage 1 or 2 ( n = 3) and no MYC N amplification ( n = 4). Overall survival (OS) and event-free survival (EFS) were, respectively, 56% and 22% (median follow-up: 36 months) for children with LOH1p compared with 97% and 94% for those without (log-rank = 10 −8 ). All except 1 of the 5 children with MYC N amplification and LOH1p relapsed and ultimately died of the disease. Among the 4 with LOH1p and no MYC N amplification, recurrence occurred in 3 (2 local, 1 metastatic), all alive in second remission after salvage therapy (12–19 months after the relapse). In multivariate analysis, LOH1p was the strongest prognostic indicator for subsequent relapse. LOH1p appears more discriminant than MYC N amplification for predicting the risk of recurrence in children with localised neuroblastoma. However, its analysis was possible in only 30% of our patients and its final impact on survival should be confirmed in larger, prospective studies in order to stratify subsequent treatment.

The aim of this study was to evaluate the feasibility, toxicity and efficacy of escalating doses of subcutaneous recombinant interleukin-6 (IL-6) in children with solid tumours in relapse. Recombinant IL-6 was administered subcutaneously once daily for 14 consecutive days, with a 14 day follow-up period. The starting dose for IL-6 was 1 microgram/kg/day and was escalated in subsequent patients groups until 10 micrograms/kg. Doses were escalated every 3 patients, provided that grade III or IV organ toxicity did not occur at the preceding dose level. Twelve patients were treated, three at each dose level. No grade 3-4 major organ toxicity was observed. Flu-like symptoms and fatigue were the most common side effects. All these symptoms resolved after the end of IL-6 administration. Significant increases in acute-phase proteins (CRP [C reactive protein], fibrinogen) and ESR (Erthrocyte sedimentation rate) were observed in all patients. Stimulatory effects on thrombocytopoiesis were observed at every dose level, and were maximal at 5 micrograms/kg and 10 microgram/kg. There was no tumour response observed during IL-6 administration. Pharmacokinetic profiles performed in 3 patients are consistent with previous reports in adults. IL-6 is a promising new cytokine for paediatric oncology, in particular to increase thrombocyte counts. We recommend that further studies in children proceed at a dose of 5-10 micrograms/kg/day in a once or, better, twice daily administration.

A pilot study of neuroblastoma mass screening was initiated in January 1990 in the Rhone French district. The expected number of births per year is 26,000. The study is designed for a 5-year period with three major goals: 1) measurement of the compliance rate of a voluntary test at 4 months of age; 2) evaluation of the technical value of high-pressure liquid chromatography (HPLC) as a screening method; and 3) detailed biological characterization of all detected tumors. 61,551 children were screened between May 1, 1990 and December 31, 1993. Participation was 69% in 1990, 81.5% in 1991, and over 83% in 1992. HPLC was a satisfactory assay method. The number of clinical examinations required for positive tests as defined in the protocol is 1 per 3,621 tests. The false positive rate is 1 per 3,583 tests. Eight neuroblastomas were discovered by-screening (one stage I, three stage II, one stage III, three stage IVs). All are alive and well but were good prognosis cases according to the main prognostic factors. Five patients were discovered before screening (so called Halo effect): one stage I, one stage III, three stage IVs. One died of disease and four are alive in complete remission after treatment. Two patients were false negative (one stage III with N-myc amplification, one stage IV with bad prognosis features) and three cases of neuroblastoma were missed because of noncompliance with the screening program. This pilot study concludes on the feasibility of a mass screening program in France. The estimated cumulative incidence of neuroblastoma at 3 years is 1 per 4,375 living births and overdiagnosis is probable. All the detected cases were of good prognosis and the false negative ones were poor prognosis cases.

Medulloblastomas is an orphan disease in adults. Standard treatment of completely removed localised adult medulloblastoma includes a craniospinal, irradiation with 36 Gy to axis and 54 Gy to whole posterior fossa. Pediatric randomized study demonstrated that a decreased dose of 24 Gy to axis with 54 Gy limited to tumoral bed gives similar result as standard therapy, provided chemotherapy is associated. May this pediatric experience be extended to adult population?

The skills of adult versus pediatric neuro-oncologists are not completely similar though additive. Because the tumors are different (mostly glioma and meningiomas in adults, versus medulloblastomas, germ cell tumors and ependymomas). And because the tolerance and expected sequelae are specific. Multidisciplinary meetings including adult and pediatric neuro oncologists are warranted to share expertise.

Introduction Malignant sacrococcygeal (SC) germ cell tumours (GCT) may be diagnosed as primary pelvic tumour or malignant recurrence of foetal SC teratoma (FSCT) operated during the neonatal period. In order to evaluate the difference between these two populations, the authors report their experience with SC-GCT registered in the French TGM 95 protocol. Population and methods The protocol comprised risk-adapted-chemotherapy (CT) followed by surgery. Standard risk (SR: localized tumour completely resected) had no adjuvant therapy. Intermediate-Risk (IR: localized tumour, incomplete or no initial surgery with αFP 15,000 ng/ml and/or metastases) received Etoposide–Ifosfamide–Cisplatin. Results Fifty-seven patients with SC-GCT, aged 0–80 months (median 16), were registered between 1995 and 2005. Nineteen patients had secondary SC-GCT after FSCT. All patients received CT: 17 IR and 1 SR after reevolution; 39 HR (25 with metastases). 51 patients underwent delayed surgery, which was incomplete in 8 patients. Evolution Seventy-two percent of the secondary SC-GCT had systematic biological follow-up. αFP increasing was the first presenting sign in 80% of the cases. Patients with secondary SC-GCT had a lower median αFP level at diagnosis, were less frequently classified as HR and received less CT. The two groups with secondary vs. primary SC-GCT had a statistically similar favourable outcome (Overall Survival: 93.8% vs. 86.2%; Event-Free Survival: 89.2 vs. 78.2%; p > 0.34 and >0.32), respectively, but with less burden of therapy. Conclusions SC-GCT has a good overall prognosis provided complete surgery is achieved and CT is administered to IR and HR patients. SC-GCT in patients followed by αFP after treatment for FSCT had less tumour extension than newly-diagnosed patients, probably because of earlier detection of the disease.

In the LMCE1 study using a single course of megatherapy most of the relapses occurred during the first 2 years after autologous bone marrow transplantation. A second pilot study (LMCE2) was therefore set up using a double harvest/double graft approach with two different megatherapy regimens. Objectives were to test the role of increased dose intensity on response status, relapse pattern and overall survival. Thirty-three patients (20 boys, 13 girls) with a median age of 53 months at first megatherapy (range, 17-202 months) entered this study. They were cases either with refractory disease in partial response after second line treatment for stage 4 neuroblastoma (n = 25) or after relapse from stage 4 (n = 5) or stage 3 disease (n = 3). All patients received Etoposid and/or Cisplatinum (or Carboplatin) containing treatments before megatherapy. The first megatherapy regimen was a combination of Tenoposid, Carmustine and Cisplatinum (or Carboplatin), the second applied Vincristin, Melphalan and Total Body Irradiation. The first harvest was scheduled 4 weeks after the last chemotherapy, the second 60 to 90 days after megatherapy. All marrows were purged in vitro by an immunomagnetic technique. Median follow up time since first megatherapy is 56 months. Response rates for evaluable patients were 65% (complete response rate: 16%) for megatherapy 1 and 60% (complete response rate: 25%) for megatherapy 2. Considering that only patients with delayed response or relapse were eligible for this pilot study the overall survival was encouraging with 36% at 2 years and still 32% at 5 years. The costs for these survival rates were high in terms of morbidity (four early and four late toxic deaths; toxic death rate: 24%). Double harvesting may have the disadvantage of delayed engraftments related in part to a disturbance of marrow microenvironment by megatherapy 1. This double megatherapy approach achieved a prolonged relapse free interval (median 11 months, range 2-31 months) in patients reaching megatherapy 2 and justifies further evaluation of concepts with consecutive dose-escalation.

Burkitt's lymphoma, a pathological entity initially described in Africa, is the most common childhood lymphoma in western countries and represents approximately 5% of all adults lymphomas. This high grade small non-cleaved diffuse lymphoma is a model with which to study the relations between cancer and viruses, the chromosomes and the genes. Burkitt's lymphoma is also a model for clinical research which allows evaluation of the dose effect concept with chemotherapy and the role of megatherapy with autologous bone marrow rescue.

A multicenter EORTC study was conducted in children with acute lymphocytic leukemia to determine whether 5 g/m2 of methotrexate (MTX) (24 h i.v. infusion, four cycles) is an appropriate dosage for obtaining CSF drug concentrations approaching the critical cytotoxic level of 10(-6) M. A total of 193 cycles were analyzed for 58 patients. At the end of the 24 h infusion, the mean MTX serum level was 65.27 +/- 33.11 microM; the mean CSF MTX level was 1.47 +/- 1.1 microM; no significant difference in CSF MTX levels was observed between patients with (n = 20) and those without i.v. Ara-C (n = 38). The mean CSF MTX/serum MTX ratio was 0.029 +/- 0.027. CSF drug concentrations greater than or equal to 10(-6) M were achieved in 81% of the courses. The highest level was 8.4 X 10(-6) M. Only 5% of patients failed to achieve this drug concentration in at least one cycle. No significant correlation was observed between blood and CSF MTX levels. Mean CSF MTX levels were comparable from one cycle to another.

PURPOSE: To determine the response rate of the malignant gliomas of childhood to an oral, daily schedule of temozolomide. PATIENTS AND METHODS: A multicenter, phase II evaluation of an oral, daily schedule of temozolomide (200 mg/m2 on 5 consecutive days) was undertaken in children with relapsed or progressive, biopsy-proven, high-grade glioma (arm A) and progressive, diffuse, intrinsic brainstem glioma (arm B). Evidence of activity was defined by radiologic evidence of a sustained reduction in tumor size on serial magnetic resonance imaging scans. RESULTS: Fifty-five patients were recruited (34 to arm A and 21 to arm B) and received 215 cycles of chemotherapy. Grade 3/4 thrombocytopenia was the most frequent toxic event (7% of cycles). Prolonged myelosuppression resulted in significant treatment delays and dose reductions (17% and 22% of cycles, respectively). Two toxic deaths were documented and were related to myelosuppression and sepsis in one patient and pneumonia in a second. The overall (best) response rate was 12% for arm A (95% confidence interval [CI], 3 to 28 in the study cohort, and 2 to 31 for eligible patients) and 5% and 6%, respectively, for arm B (95% CI, 0 to 26 in the study cohort, and 0 to 27 for eligible patients). Stabilization of disease was also documented and was most noteworthy for brainstem gliomas, where two patients achieved both radiologic static disease and discontinued steroid medication. CONCLUSION: Despite moderate toxicity, objective response rates to temozolomide have been low, indicating that temozolomide has minimal activity in the high-grade gliomas of childhood.

Background To determine the effectiveness of multiagent chemotherapy as sole post-operative treatment of supratentorial central nervous system (CNS) embryonal tumors in young children. Procedure The data of 25 children under 5 years of age diagnosed with supratentorial embryonal tumors (17 primitive neuroectodermal tumors, four pinealoblastomas, and four medulloepitheliomas) treated exclusively by postoperative chemotherapy (CT) between 1990 and 1997 were reviewed. Results Fifteen tumors were hemispheric and 10 were deeply seated. Four children presented with disseminated leptomeningeal disease. Total resection was performed in nine patients, subtotal in 9, partial in 3, and a diagnostic biopsy only in 2. Two children did not undergo surgery. Twenty-four children relapsed with a median time of 5.5 months. The median overall survival was 12 months, and the 2-, and 5- year survivals were 30 and 14y, respectively. The 2- year disease-free survival was 4%. There was a significantly worse prognosis in patients undergoing incomplete resection and in the group with deeply situated tumors. Four relapses were treated by second surgery followed by high-dose chemotherapy and radiotherapy. Two of them remain in CR2, and all these children are free of late sequelae. Conclusions CT alone failed to maintain disease-free survival in most of the children, although, disease progression was delayed to some extent. Children under 5 years with supratentorial embryonal tumors should undergo total surgical resection if possible. Med Pediatr Oncol 2002;38:83–90. © 2002 Wiley-Liss, Inc.

The Lyon-Marseille-Curie-Est (LMCE) of France cooperative group has previously reported successive series of unselected stage four children older than 1 year at diagnosis with metastatic neuroblastoma (LMCE 1 and 3). The goal of LMCE 5 study was to increase progression free survival rate as compared to LMCE 1 and 3. Based on improvements reported with post induction chemotherapy, the LMCE 5 used post induction for all children, but omitted total body irradiation and immunomagnetic purging in megatherapy regimen for all children. Twenty-five sequentially diagnosed children received an induction regimen which compared with previous induction included an increased dose of etoposide and cyclophosphamide, delivered similar dose of cisplatinum, and deleted doxorubicin and vincristin. After surgery treatment was stratified based on response and eligible children received etoposide carboplatin (LMCE 5A : n=10)±doxorubicin (LMCE 5B–C n=13) followed by megatherapy (melphalan without total body irradiation and unpurged peripheral blood stem cell rescue). The increase in drug doses during induction did not improve remission rate. The progression free survival at 6 years is 8%. It is significantly worse than LMCE 3, and equivalent to LMCE 1 study though toxic death rate has decreased with increasing experience. Failure to improve the response rate during induction and reducing the megatherapy regimen may be the main factors in this disappointing result. Modified strategies for induction, non toxic alternative to total body irradiation, and post megatherapy regimen should be developed. British Journal of Cancer (2002) 87, 1197–1203. doi:10.1038/sj.bjc.6600627 www.bjcancer.com © 2002 Cancer Research UK

The previous SFOP TGM85 and TGM90 studies showed that carboplatin (400 mg/m2) was less efficient that cisplatin (100 mg/m2), that patients with AFP levels over 15000 ng/ml had a worse outcome, and that the VIP regimen (VP 16, Ifosfamide, cisplatin) was an efficient salvage therapy [1–3]. Based on these results, the SFOP developed the TGM95 protocol, a cisplatin-based chemotherapy adapted to initial resection, serum AFP and presence of metastases. Patients are stratified into three risk groups with the following guidelines: low risk (LR) patients with complete resection of a localized tumour (pSl): “watch and wait” with chemotherapy only in cases of tumour marker increase; median risk (MR) patients: non metastatic incompletely resected or unresectable tumour with AFP less than 15000: VBP (Vinblastine, Bleomycine, cisplatin) regimen; high risk (HR) patients: AFP 15000 or more, and/or metastasis: VIP regimen. In both groups, patients received two additional courses of chemotherapy after normalization of tumour markers. The residual tumour or the organ initially involved (if not previously done) were excised after normalization of tumour markers.

In the SFOP TC-90 and TC-92 protocols, patients with intracranial germinomas and secreting germ cell tumours (sGCT) were treated with a combination of chemotherapy and focal radiotherapy. One chemotherapy cycle included alternating Carboplatin-VP16 and Ifosfamide-VP16. Germinoma patients received two cycles followed by 40 Gy focal radiotherapy, and sGCT three or four cycles followed by focal 55 Gy. Metastatic patients received craniospinal radiotherapy.

The presence of multifocal or diffuse nephrogenic rests (NRs) in one or both kidneys is termed nephroblastomatosis (Nbm). Nbm may be a predisposing factor for Wilms' tumour (WT). The aim of this retrospective study was to evaluate the impact of Nbm on the outcome of WT in children. We assessed the outcome of 81 children with Wilms tumours and practical implications of Nbm in the treatment and follow-up. All the pathology slides have been reviewed in 1997. 63 had WT without Nbm (group A) and 18 had WT associated with Nbm (group B). There was no statistical difference between the two groups according to the age at diagnosis and histology. Clinical abnormalities were more frequent in group B (33 versus 8%). There was no statistical difference between the percentage of stage IV in both groups, but bilaterality (stage V) was present only in the group B. Relapse was observed in 20/81 patients (25%): 11 (17%) in group A and 9 (50%) in group B. Mean delay of relapse was longer (25 months) in group B than in group A (10 months). For the whole population, with a median follow-up of 9 years, the event-free survival (EFS) and the overall survival (OS) probabilities were respectively 74%±10 and 83%±9 at 120 months. The difference in EFS between groups A (82±9%) and B (38%±29) was significant ( P =0.004). The discovery of Nbm in the non-tumoral part of the kidney with WT can be an adverse factor and in particular favours the subsequent development of a new Wilms tumour. It justifies separate follow-up guidelines.