D. Plantaz

High-dose Chemotherapy with Carboplatin, Etoposide and Cyclophosphamide Followed by a Haematopoietic Stem Cell Rescue in Patients with High-risk Retinoblastoma: a SFOP and SFGM Study

This study investigates the role of high-dose chemotherapy with haematopoietic stem cell rescue as consolidation treatment in high-risk retinoblastoma (extraocular disease at diagnosis or relapse or invasion of cut end of optic nerve). 25 patients received high-dose chemotherapy including carboplatin (250 mg/m2/day from day 1 to day 5 for the 6 first patients and 350 mg/m2/day from day 1 to day 5 for the other patients), etoposide (350 mg/m2/day from day 1 to day 5) and cyclophosphamide (1.6 g/m2/day from day 2 to day 5) (CARBOPEC) followed by autologous haematopoietic stem cell rescue. 19 patients received this drug combination for chemosensitive extraocular relapse. The other 6 patients with histological high-risk factors were given this treatment as consolidation after enucleation and conventional chemotherapy. The three year disease-free survival was 67.1%. In 7 of the 9 relapsing patients, the first site of relapse was the central nervous system. All patients with central nervous system disease died except one. The main toxicity was haematological and digestive (mucositis and diarrhoea). 2 of the 13 evaluable patients had grade III and IV ototoxicity. One patient experienced an acute grade I reversible cardiotoxicity. The CARBOPEC regimen seems to be a promising therapeutic strategy in patients with high-risk retinoblastoma, especially those with bone and/or bone marrow involvement. This treatment did not improve the outcome of patients with central nervous system disease.

Improving survival in recurrent medulloblastoma: earlier detection, better treatment or still an impasse?

Early detection of relapse has been advocated to improve survival in children with recurrent medulloblastoma. However, the prognostic factors and the longer term outcome of these patients remains unclear. Pattern of recurrences were analysed in three consecutive protocols of the Société Française dOncologie Pédiatrique (1985-91). A uniform surveillance programme including repeated lumbar puncture combined with computerized tomography (CT) or magnetic resonance imaging (MRI) scan was applied for all registered patients. Forty-six out of 116 patients had progressive or recurrent disease. The median time from diagnosis to recurrence was 10.5 months and 76% relapses occurred during the first 2 years. Seventeen patients had asymptomatic relapses that were detected by the surveillance protocol. Forty-one patients were treated at time of progression. Twenty-three responded to salvage therapy and 11 achieved a second complete remission. The median survival time after progression was 5 months (<1-41 months), and only two patients remained alive at time of follow-up. Length of survival is primarily related to some specific patterns of relapse (time from diagnosis to recurrence, circumstances of relapse, extent of relapse) and to the response to salvage therapy. No evidence of long-term benefit appeared from any form of treatment.

Carboplatin before and during radiation therapy for the treatment of malignant brain stem tumours: a study by the Société Française d'Oncologie Pédiatrique.

Childhood malignant brain stem tumours have a very poor prognosis with a median survival of 9 months despite radiotherapy. No chemotherapy has improved survival. However, carboplatin has been reported to have activity in glial tumours as well as antitumour synergy with radiation. Our aims were to test the response rate of these tumours to carboplatin alone and to evaluate the efficacy on survival of carboplatin alone followed by concurrent carboplatin and radiotherapy. Patients younger than 16 years with typical clinical and radiological presentation of infiltrating brain stem tumour, as well as histologically-documented cases in the atypical forms, were eligible. Two courses of carboplatin (1050 mg/m2 over 3 days) were administered initially. This treatment was followed by a chemoradiotherapy phase including five weekly carboplatin courses (200 mg/m2) and conventional radiotherapy. 38 eligible patients were included. No tumour response was observed after the initial phase. This schedule of first-line carboplatin followed by concurrent carboplatin and radiotherapy did not improve survival.

Localised and unresectable neuroblastoma in infants: excellent outcome with low-dose primary chemotherapy

The purpose of this study was to evaluate the efficacy of low-dose chemotherapy in infants with localised and unresectable neuroblastoma (NB). All consecutive infants with localised NB and no N-myc amplification were eligible in the SFOP-NBL 94 study. Primary tumour was deemed as unresectable according to imaging data showing any risk of immediate resection. Diagnostic procedures and staging were conducted according to INSS recommendations. For children, provided that they had no threatening symptom (i.e. vital risk or dumb-bell NB with neurologic deficit), chemotherapy consisted in low-dose cyclophosphamide (5u2009mg−1kgu2009day−1 × 5 days) and vincristine (0.05u2009mgu2009kg−1 at day 1)–CV and repeated one to three times every 2 weeks until surgical excision can be safely performed. No postoperative treatment was given. Between January 1995 and December 1999, 134 consecutive infants with localised NB were registered in the study, of whom 39 had an unresectable NB without N-myc amplification. Among them 28 had no threatening symptom and received CV according to the protocol. Objective response was observed in 14 (50%) and the other 14 were given second-line chemotherapy because of no response. Surgery was attempted in 38 patients including 14 after CV alone, leading to complete resection in 23. Relapses occurred in four patients all local. Survival and event-free survival were 100 and 90±5% with a median follow-up of 55 months (range 33–93). In conclusion primary low-dose chemotherapy without anthracyclines is efficient in about half of the infants presenting with an unresectable NB and no N-myc amplification, allowing excellent survival rates without jeopardising their long-term outcome even for nonresponding patients who received standard regimen.

Unresectable localized neuroblastoma: improved survival after primary chemotherapy including carboplatin-etoposide

Neuroblastomas (NBs) were assessed according to INSS recommendations including MIBG scan and extensive bone marrow staging to eliminate metastatic spread. Patients with unresectable tumour received primary chemotherapy including two courses of carboplatin-etoposide (CE) and two of vincristine-cyclophosphamide-doxorubicin (CAdO). Post-operative treatment was to be given only in children over 1 year of age at diagnosis who had residual disease or lymph node (LN) involvement. Between 1990 and 1994, 130 consecutive children were registered. In comparison with resectable primaries, these tumours were more commonly abdominal, larger and associated with N-myc amplification (NMA). Complete, very good and partial response (CR, VGPR, PR) to CE were, respectively, 1%, 7% and 44%, overall response rate (RR) to two courses of CE and two courses of CAdO was 71%, and the tumour could be removed in all but four of the children. The toxicity was manageable. The 5-year overall survival (OS) and event-free survival (EFS) were, respectively, 88% and 78% with a median follow-up of 38 months. In multivariate analysis, only NMA and LN involvement adversely influenced the outcome, particularly NMA. Children with unresectable NBs and no NMA fared as well as children with resectable ones as OS were, respectively, 95% and 99% and EFS 89% and 91%. Our data show encouraging results in localized but unresectable NBs as 90% of children may be considered as definitely cured, especially those without NMA.

Kinetics of hematopoietic progenitor cell release induced by G-CSF-alone in children with solid tumors and leukemias

The kinetics of peripheral blood progenitor cell (PBPC) release induced by G-CSF-alone at 10u2009μg/kg/day were monitored daily in 42 children with solid tumors and leukemias. Median 16- and 27-fold enrichment of circulating CD34+ cells and granulocyte–macrophage colony-forming units (CFU-GM) was noted with peak values occurring after the 4th or the 5th G-CSF dose. Individual values of PBCD34+ cell levels in patients with solid tumors were not significantly different after the 4th and after the 5th dose. The day-of-collection PBCD34+ cell concentration was related to the harvested CD34+ cell (Pu2009=u20090.0001) and CFU-GM numbers (Pu2009=u20090.0001). No correlations were found between PBPC enrichment and either patient age, body weight, diagnosis or pre-mobilization treatment duration. The median numbers of 1.1u2009×u2009106 CD34+ cells/kg and 28.1u2009×u2009104 CFU-GM/kg were derived from one patient’s blood volume processed. Nineteen patients received G-CSF-alone primed grafts and had successful engraftment. Our data indicate that in 88% of children a single standard leukapheresis is sufficient to obtain a minimum graft (2u2009×u2009106 CD34+ cell and/or 10u2009×u2009104 CGU-GM per kg) whether undertaken after the 4th dose of G-CSF or the 5th.

IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951

The added value of IKZF1 gene deletion (IKZF1del) as a stratifying criterion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is still debated. We performed a comprehensive analysis of the impact of IKZF1del in a large cohort of children (n=1223) with BCR-ABL1-negative BCP-ALL treated in the EORTC-CLG trial 58951. Patients with IKZF1del had a lower 8-year event-free survival (EFS, 67.7% versus 86.5%; hazard ratio (HR)=2.41; 95% confidence interval (CI)=1.75–3.32; P<0.001). Importantly, despite association with high-risk features such as high minimal residual disease, IKZF1del remained significantly predictive in multivariate analyses. Analysis by genetic subtype showed that IKZF1del increased risk only in the high hyperdiploid ALLs (HR=2.57; 95% CI=1.19–5.55; P=0.013) and in ‘B-other‘ ALLs, that is, lacking classifying genetic lesions (HR=2.22; 95% CI=1.45–3.39; P<0.001), the latter having then a dramatically low 8-year EFS (56.4; 95% CI=44.6-66.7). Among IKZF1del-positive patients randomized for vincristine-steroid pulses during maintenance, those receiving pulses had a significantly higher 8-year EFS (93.3; 95% CI=61.3–99.0 versus 42.1; 95% CI=20.4–62.5). Thus, IKZF1del retains independent prognostic significance in the context of current risk-adapted protocols, and is associated with a dismal outcome in ‘B-other‘ ALL. Addition of vincristine-steroid pulses during maintenance may specifically benefit to IKZF1del patients in preventing relapses.

Metastatic medulloblastoma: the experience of the French cooperative M7 group

A retrospective analysis was performed to determine the outcome of children with metastatic medulloblastoma given a standardised treatment programme. Of 68 consecutive patients treated in the French M7 protocol for medulloblastoma, 23 presented with metastatic disease. They were uniformly treated with surgery, and the same protocol of chemotherapy and craniospinal radiotherapy. The 7-year relapse-free survival rate is 43% for metastatic patients compared to 68% for patients with localised disease. Survival did not correlate with age, sex, location of metastases, extent of initial surgery and the dose of radiation therapy on the posterior fossa. Survival did correlate with the dose to the cranial field with a threshold dose of 30 Gy. Patients with metastatic disease have a worse prognosis and require more aggressive therapies at initial presentation. The prognostic impact of the different sites of metastatic disease requires further evaluation in cooperative studies.

Use of G‐CSF alone to mobilize peripheral blood stem cells for collection from children

Summary We report the data of 19 children with neuroblastoma (NB) or Ewings sarcoma (EW) who had peripheral blood stem cells (PBSCs) harvested after mobilization by: (1) cyclophosphamide (CY) + etoposide + G‐CSF, (2) CY+GM‐CSF, or (3) G‐CSF alon. There were no consistent differences in the number of PBSCs collected following these three different mobilization regimens as assessed by CFU‐GM. 17 patients were reinfused with PBSCs after myeloablative therapy and had successful haemopoietic recovery. These results show that in children with solid tumours such as NB or EW a sufficient number of PBSCs can be collected after G‐CSF alone, and that PBSCs collected following stimulation by G‐CSF alone are as effective in reconstituting haemopoiesis as those collected after mobilizing chemotherapy + HGFs.

Adverse outcome of infants with metastatic neuroblastoma, MYCN amplification and/or bone lesions: results of the French society of pediatric oncology.

To assess the relevance of MYCN amplification and bone lesions in stage 4 neuroblastoma (NB) in infants aged <1 year, 51 infants with stage 4 NB were enrolled. Three groups of patients were defined according to the type of metastases and the resectability of the primary tumour. Group I comprised 21 infants with radiologically detectable bone lesions, Group II 22 patients with an unresectable primary tumour and Group III eight patients with only metaiodobenzylguanidine (MIBG) skeletal uptake. MYCN oncogene content was assayed in 47/51 tumours and found to be amplified in 17 (37%). The 5-year event-free survival (EFS) rate of these 51 infants was 64.1% (± 7.1%). In a univariate analysis, bone lesions, MYCN amplification, urinary vanillylmandelic/homovanillic acid ratio and serum ferritin levels adversely influenced outcome. In the multivariate analysis, radiologically detectable bone lesions were the most powerful unfavourable prognostic indicator: the EFS rate was 27.2% for these infants compared to 90% for infants without bone lesions (P < 0.0001). Our data emphasize the poor prognosis of infants affected by stage 4 NB with bone lesions, especially when associated with MYCN amplification. Given the poor results in this group whatever the treatment, new therapeutic approaches need to be investigated in the future.