Busulfan-melphalan in high-risk neuroblastoma: the 30-year experience of a single institution.

High-dose chemotherapy (HDC) was investigated in high-risk neuroblastoma (HR-NBL) to reduce the risk of relapse. We report the results of the 30-year experience of a cohort of patients with HR-NBL treated with high-dose (HD) busulfan (Bu)-containing regimens. From 1980 to 2009, 215 patients aged >1 year with stage 4 NBL were treated with HD Bu-containing regimens at Gustave Roussy. These data were prospectively recorded in the Pediatric Transplantation Database. The median age at diagnosis was 40 months (12-218 months). All patients had a stage 4 neuroblastoma. NMYC amplification was displayed in 24% of the tumors. The hematopoietic support consisted of bone marrow or PBSCs in 46% and 49% of patients, respectively. The 5-year event-free survival and overall survival rates of the whole cohort were 35.1% and 40%, respectively. Age at diagnosis, bone marrow involvement and tumor response after induction chemotherapy were significant prognostic factors. Toxicity was manageable and decreased over time, owing to both PBSC administration and better supportive care. Based on this experience, HD Bu-melphalan (Mel) has been implemented in Europe and compared with Carboplatin-Etoposide-Mel in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized protocol. It has now become the standard HDC in the SIOPEN HR strategy.

Tandem high-dose chemotherapy with thiotepa and busulfan-melphalan and autologous stem cell transplantation in very high-risk neuroblastoma patients.

High-risk neuroblastoma is characterised by poor long-term survival, especially for very high-risk (VHR) patients (poor response of metastases after induction therapy). We report the results of an intensified high-dose chemotherapy (HDC) strategy to improve the prognosis of VHR patients. This strategy was based on tandem HDC with thiotepa and busulfan-melphalan (Bu-Mel) followed by autologous stem cell transplantation (ASCT). All data were prospectively recorded in the Gustave Roussy Paediatric ASCT database. From April 2004 to August 2011, 26 patients were eligible for tandem HDC. The median age at diagnosis was 4.4 years (1-15.9). All patients had metastatic disease. MYCN was amplified in 5/26 tumours. Despite the cumulative toxicity of alkylating agents, the toxicity of the intensified HDC strategy was manageable. Thiotepa-related toxicity was mainly digestive, whereas sinusoidal obstruction syndrome was the main toxicity observed after Bu-Mel. The 3-year event-free survival of this cohort was 37.3% (21.3-56.7). This strategy will be compared with combined (131)I-mIBG/Bu-Mel in the upcoming SIOPEN VHR Neuroblastoma Protocol.

[A multidisciplinary consultation for children with brain tumors]. / Une consultation multidisciplinaire pour les enfants traités pour une tumeur cérébrale.

UNLABELLED: School achievement of children with brain tumors is hampered by progressive neurologic and cognitive sequelae. To help the children and their family, we have created in 1997 a multidisciplinary consultation together with Necker's hospital. MATERIAL AND METHODS: The study describes the organization of the consultation and analyses the files of 69 children seen between September 2001 and June 2002. RESULTS AND CONCLUSION: The authors conclude that this consultation is an irreplaceable mean to coordinate the complex rehabilitation process of a child treated for a brain tumor.

[Treatment of childhood cancer in Africa. Action of the Franco-African childhood cancer group]. / Le traitement des cancers de l'enfant en Afrique. Travaux du groupe franco-africain d'oncologie pédiatrique.

The childhood cancer survival rate is currently 75% in industrialized countries. Rates in developing countries are much lower. The Franco-African Childhood Cancer Group (French acronym, GFAOP) was founded in 2000 with aim of reducing this unfavorable situation in Africa. The GFAOP has developed two forms of action. The main form consists of organizing two- to twelve-month training sessions for physicians and nurses in France and Morocco. The other form involves assessing the feasibility of modern treatment protocols for various cancers in Africa. The first feasibility trials were carried out on nephroblastoma and Burkitt's lymphoma in 12 pilot units in North Africa, West Africa, and Madagascar. In the first study from 2001 to 2005 we treated 306 cases of Burkitt's lymphoma using French LMB protocols adapted to the African setting and achieved a survival rate of 61%. A second study started in 2005 using Endoxan alone achieved a highly satisfactory survival rate of 73% for neuroblastoma in all stages except bilateral. Altogether from 2001 to 2007 more than 1000 cases of nephroblastoma and Burkitt's lymphoma were treated in African hospitals by African doctors and nurses. No patients were transferred to Europe. The GFAOP supplied drugs when necessary and took care of most travel expenses. African and French doctors worked together on protocol design, trial management, and data analysis. These promising results show that the latest therapeutic techniques can be used to treat childhood cancer in Africa by adapting the protocol to conditions in developing countries. Sanofi-Aventis Laboratories in association with the International Union against Cancer has launched a major campaign to improve Pediatric Oncology in developing countries. Projects in four GFAOP units are being financed through this campaign. In 2006 the GFAOP began assessment of two new treatment protocols, i.e., one for acute lymphoblastic leukemia and the other for Hodgkin's disease. Two other projects are being planned, i.e., one for treatment of retinoblastoma and the other for treatment of some types of brain tumors.

High-grade glioma in children under 5 years of age: a chemotherapy only approach with the BBSFOP protocol.

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.

Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies.

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.

Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: a multicenter trial of the French Society of Pediatric Oncology.

PURPOSE: To evaluate a strategy that avoids radiotherapy in first-line treatment in children under 5 years of age with brain or posterior fossa ependymoma, by exclusively administering 16 months of adjuvant multiagent chemotherapy after surgery. PATIENTS AND METHODS: Between June 1990 and October 1998, 73 children with ependymoma (82% with high-grade tumors) were enrolled onto this multicenter trial. Children received adjuvant conventional chemotherapy after surgery consisting of seven cycles of three courses alternating two drugs at each course (procarbazine and carboplatin, etoposide and cisplatin, vincristine and cyclophosphamide) over a year and a half. Systematic irradiation was not envisaged at the end of chemotherapy. In the event of relapse or progression, salvage treatment consisted of a second surgical procedure followed by local irradiation with or without second-line chemotherapy. RESULTS: Conventional chemotherapy was well tolerated and could be administered in outpatient clinics. No radiologically documented response to chemotherapy more than 50% was observed. With a median follow-up of 4.7 years (range, 5 months to 8 years), the 4-year progression-free survival rate in this series was 22% (95% confidence interval [CI], 13% to 43%) and the overall survival rate was 59% (95% CI, 47% to 71%). Overall, 40% (95% CI, 29% to 51%) of the patients were alive having never received radiotherapy 2 years after the initiation of chemotherapy and 23% (95% CI, 14% to 35%) were still alive at 4 years without recourse to this modality. In the multivariate analysis, the two factors associated with a favorable outcome were a supratentorial tumor location (P =.0004) and complete surgery (P =.0009). Overall survival at 4 years was 74% (95% CI, 59% to 86%) for the patients in whom resection was radiologically complete and 35% (95% CI, 18% to 56%) for the patients with incomplete resection. CONCLUSION: A significant proportion of children with ependymoma can avoid radiotherapy with prolonged adjuvant chemotherapy. Deferring irradiation at the time of relapse did not compromise overall survival of the entire patient population.

When do children with optic pathway tumours need treatment? An oncological perspective in 106 patients treated in a single centre.

UNLABELLED: Progression patterns of optic pathway tumours (OPT) need to be precisely defined for treatment planning. In patients with neurofibromatosis type 1 (NF1), this disease is usually indolent and the available literature rarely reports progression after the age of 6 years. In patients without NF1, the disease course seems to be less favourable. We reviewed the clinical and radiological files of 106 children referred to our institution for the treatment of a symptomatic OPT since 1980. NF1 was present in 51 of them. Progression patterns in children with NF1 differed markedly from those in the other patients. A total of 83 children had tumour extension beyond the chiasm (Dodge type III). Children with NF1 had progressive tumours later during follow-up (47% after the age of 6 years), had more often proptosis and infiltrating tumours but less frequently nystagmus or increased intracranial pressure. 32 children were not treated at diagnosis because they had only mild symptoms related to the OPT. In these patients, progression occurred more often in children without than with NF1 (12/12 versus 12/20 respectively, P = 0.04). A high number of patients needed treatment for progression or severe symptoms after 6 years of age. Of the patients, 33% needed treatment for progression or severe symptoms after 6 years of age. CONCLUSION: Progression patterns of optic pathway tumours in children with neurofibromatosis type 1 differ markedly from those in other patients. This study emphasises the need for prolonged follow-up of children with optic pathway tumours, especially in neurofibromatosis type 1.

Long-term intellectual outcome in children with posterior fossa tumors according to radiation doses and volumes.

PURPOSE: To analyze the relationship between craniospinal irradiation (CSI) and intellectual outcome in children with posterior fossa (PF) tumors. METHODS AND MATERIALS: A neuropsychological evaluation was performed retrospectively in 31 children, aged 5-15 years, who had received radiotherapy for PF tumors, and who had been off therapy for at least 1 year. Factors evaluated for impact on intellectual outcome were: socioeconomic status, disease presentation, histology, complications, chemotherapy, age at radiotherapy, interval between radiotherapy and testing, and radiation doses and volumes. Patients were divided into 3 subgroups according to the CSI doses (0 Gy [i.e., PF irradiation only], 25 Gy, and 35 Gy), with 11, 11, and 9 patients, respectively. RESULTS: Long-term cognitive impairment occurred in most of the patients, even after PF irradiation only. Moreover, there was a significant correlation between the full-scale IQ score (FSIQ) and the CSI dose, with mean FSIQ scores at 84.5 (SD = 14.0), 76.9 (SD = 16.6), and 63.7 (SD = 15.4) for 0 Gy, 25 Gy, and 35 Gy of CS1, respectively. A marked drop in verbal comprehension scores was noted in children who had received the higher dose. CONCLUSION: This preliminary study further supports the rationale for de-escalation of CSI doses and volumes in standard-risk PF tumors.

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment.

The variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer.

Primitive cerebral neuroectodermal tumors excluding medulloblastomas: a retrospective study of 30 cases.

We present a retrospective study of 30 cases of primitive cerebral neuroectodermal tumors (PNET), excluding medulloblastomas, referred to us postoperatively for additional therapy to evaluate prognostic factors and treatment efficiency. The histologic types were: pinealoblastomas (n = 7); ependymoblastomas (n = 2); medulloepitheliomas (n = 4), and other PNET (n = 17). The tumor was located in the supratentorial area in 24 patients and in the posterior fossa in 6 patients. Among the supratentorial tumors, 8 were metastatic. Maximal surgical resection was performed. Sixteen of 30 patients had no measurable disease after surgery and were considered as standard-risk (SR) cases, and 14 with a local residue or metastasis as high-risk (HR) cases. The objective of postsurgical treatment was to avoid radiotherapy in children below 4 years of age. It consisted of radiotherapy alone in 6 patients, chemotherapy alone in 17, and radiotherapy with chemotherapy in 7. Furthermore, high-dose chemotherapy (busulfan, thiotepa) and autologous bone marrow transplantation, performed in 6 patients, yielded a response rate of 3/6. Event-free survival (EFS) of SR patients was 37% at 3 years (95% confidence interval (CI) 14-60%) and overall survival 44% (95% CI 26-62%). Only 1 of the HR patients achieved a complete remission and all of them died early. The critical prognostic factors appear to be the completeness of initial surgical resection and absence of metastasis. These tumors have a poor prognosis. Novel strategies (high-dose chemotherapy) are needed to improve their outcome because the children concerned are very young and the effects of radiotherapy are particularly deleterious when tumors are situated in the supratentorial area.

Radiation and genetic factors in the risk of second malignant neoplasms after a first cancer in childhood.

BACKGROUND: Radiotherapy and chemotherapy are associated with an increased risk of second malignant neoplasm (SMN). An association between SMN and familial aggregation has also been shown. The aim of this study was to investigate the role of familial factors in the risk of SMN and their potential interaction with the effect of treatment. METHODS: We devised a case-control study of 25 children with SMN (cases) and 96 children with no SMN after a cancer treatment (controls), taken from a cohort of 649 children treated at our institution between 1953 and 1985. A complete family history was obtained for patients and controls and a familial index defined to evaluate the degree of familial aggregation. The radiation dose given at 151 sites in the body was estimated for each radiotherapy course for each child. FINDINGS: Among family members of the 25 SMN cases, there were ten with early-onset (< or = 45 years) cancer, compared with eight among relatives of the 96 controls. Compared with patients who had no family history of early-onset cancer, those with one or more affected family members had an odds ratio for SMN of 4.7 (95% CI 1.3-17.1; p = 0.02). Adjustment for local radiation dose and exclusion of patients known to be predisposed to SMN (carriers of p53 mutation and those with Recklinghausen's disease) did not affect this risk substantially. INTERPRETATION: Both genetic factors and exposure to ionising radiation have independent effects on the risk of SMN. Follow-up of children treated for cancer should be especially vigilant when there is a family history of early-onset cancer.

Quality control of low dose craniospinal irradiation for low risk medulloblastoma.

Between July 1984 and May 1990, 25 children (median age 9 years) classified as low risk medulloblastoma were treated post-operatively with low dose craniospinal irradiation (25 Gy) followed by a boost to the posterior fossa (total dose 55 Gy), with or without chemotherapy. Simulator and portal films were reviewed for all patients. Doses delivered at the mid cerebral and spinal axis, anterior vertebral body, field junctions and posterior fossa were recalculated and correlated with outcome. Three children were excluded because of inadequate data leaving 22 cases for study. The 5-year actuarial survival is 55%. Nine recurrences and one second tumour (astrocytoma) were observed. Sites of recurrence were either in the posterior fossa (5), in the brain (3), in the spinal axis (1), or combined (2). The dose delivered was within +/- 5% of that prescribed to the brain in 21/22 cases, and to the posterior fossa and the anterior surface of the vertebral body in 17/22 cases. The only patient who received less than 95% of the prescribed dose to the brain (23 Gy) failed in the subfrontal area and olfactory plate. One of the five patients who received less than 95% of the prescribed dose to the posterior fossa (50.3 Gy) failed at the primary site. None of the five patients who received less than 95% of the dose to the spinal axis failed. Quality control of radiation treatment showed that failures could not be correlated with incorrect technique.

Low-dose radiation therapy and reduced chemotherapy in childhood Hodgkin's disease: the experience of the French Society of Pediatric Oncology.

PURPOSE: With the aim of decreasing undesirable side effects of therapy, we investigated the reduction of both chemotherapy and radiation therapy (RT) in children with Hodgkin's disease, and compared Adriamycin (doxorubicin; Farmitalia Carlo Erba, Rueil-Malmaison, France), bleomycin, vinblastine, and dacarbazine (ABVD) alone to mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and ABVD in favorable cases and assessed the effectiveness of low-dose RT (20 Gy) after good response to chemotherapy. PATIENTS AND METHODS: A French national study began in 1982 that included 238 pediatric patients with Hodgkin's disease. Initial staging was clinical and without laparotomy. In patients with localized disease (IA-IIA), an equivalence trial compared the effectiveness of four cycles of ABVD with two cycles of ABVD that were alternated with two cycles of MOPP. Patients with more advanced disease (IB-IIB-III-IV) received three courses of MOPP that was alternated with three courses of ABVD. All of the patients who achieved a good remission after chemotherapy were administered 20 Gy RT, which was limited to the initially involved areas for localized disease, and encompassed the paraaortic nodes and the spleen as well for more advanced stages. When a good remission was not obtained, 40 Gy RT was administered. RESULTS: At the completion of chemotherapy, 227 patients (97%) were considered good responders, whereas 11 did not achieve a good remission. With a median follow-up of 6 years, the 6-year actuarial survival was 92% and the disease-free survival was 86%. The relapse-free survival in favorable stages was 90% in the ABVD arm and was 87% in the MOPP and ABVD arm. In June 1987, inclusion of stage IV patients was discontinued because of poor results. CONCLUSIONS: Present findings indicate that (1) in favorable stages, ABVD alone and alternating MOPP and ABVD are equivalent, and (2) chemotherapy followed by 20 Gy RT represents a valid therapeutic approach in the vast majority of children with Hodgkin's disease.

Long-term risk of second malignant neoplasm after a cancer in childhood.

The risk of subsequent second malignant neoplasm was studied in a cohort of 634 patients, treated for a childhood cancer at the Gustave Roussy Institute between 1942 and 1969, and in complete remission five years after diagnosis. The most frequent types of first primary cancers (FPC) were Wilms' tumours (28% of the children), neuroblastomas (16%), lymphomas (12%) and soft tissue sarcomas (11%). Median follow-up duration after FPC was 19 years. Thirty-two patients (obs = 32) developed a total of 35 second cancers. Bone, thyroid, connective tissues and skin were the most frequent types of second cancer, with six patients for each type. The average annual incidence of second cancer was 0.36%. The average annual incidence for the periods 5-9, 10-14, 15-19, 20-24 and 25+ years after FPC was respectively 0.16%, 0.34%, 0.36%, 0.71% and 1.18%. The cumulative incidence of second cancer for the periods 5-20, 5-25 and 5-30 years after FPC was, respectively, 4.3% (95% CI: 2.8-6.6%), 7.8% (95% CI: 5.1-11.8%) and 13.0% (95% CI: 8.2-20.0%). The expected number of cancers in the cohort, computed from Danish cancer incidence data, was exp = 2.2. When compared to this expected number, the average annual excess incidence of second cancer, defined as obs-exp divided by the number of person years of observation, was 0.33%. This rose from 0.15% for the period 5-9 years after FPC to 1.09% for the period beginning 25 years after FPC. The standardised incidence ratio of second cancer (i.e. obs/exp) was 15 (95% CI: 10-21), and was fairly constant in the period extending from 15 to 20 years after FPC diagnosis. Obs/exp was equal to 25 for the patients who had had chemotherapy and equal to 9 for those who had not. Cyclophosphamide seemed less carcinogenic than the other alkylating agents. Obs/exp was similar for the patients who had received radiotherapy and for those who had not. The risk of cancer increased with age in the reference population and increased faster in the cohort, because the standardised incidence ratio is constant over a long period.

Le traitement en Afrique des cancers de l'enfant - Travaux du Groupe Franco-Africain d'Oncologie Pediatrique

Les cancers de l'enfant sont actuellement gueris dans 75des cas; dans les pays developpes. Dans les pays en developpement; les resultats sont beaucoup moins bons. Le Groupe Franco-Africain d'Oncologie Pediatrique (GFAOP) s'est constitue en 2000 avec pour objectif de redresser cette situation defavorable enAfrique. Les actions du GFAOP comprennent; d'une part la formation des medecins et des infirmieres avant tout par des stages en France et au Maroc; d'autre part des essais de traitement par des protocoles adaptes des lymphomes de Burkitt et des nephro- blastomes dans douze unites pilotes situees en Afrique du Nord; Afrique de l'Ouest et a Madagascar. Dans une premiere etude 2001-2005; 61des lymphomes de Burkitt ont gueri. Une seconde etude a commence en 2005 avec un traitement a base d'Endoxan seul. Pour les nephroblastomes; le taux de guerison; 73; est tres satisfaisant. Plus de 1000 cas de nephroblastome et de lymphome de Burkitt ont deja ete traites dans ces conditions de 2001 a 2007; tous en Afrique; dans les hopitaux africains; par desmedecins et des infirmieres africains. Ces resultats encourageants permettent de conclure a la faisabilite du traitement des cancers de l'enfant en Afrique; grace a des traitementsmodernes; adaptes de protocoles utilises dans les pays developpes. Le laboratoire Sanofi-Aventis; associe a l'Union Internationale Contre le Cancer; a lance une grande entreprise d'aide a l'Oncologie Pediatrique dans les pays en voie de developpement.Quatre projets d'unites du GFAOP sont ainsi finances. Le GFAOP a lance en 2006 deux nouveaux protocoles : le traitement des leucemies aigues lymphoblastiques et celui de la maladie de Hodgkin. Deux autres projets sont en preparation : le traitement des retinoblastomes et celui de certaines tumeurs cerebrales