Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR.

BACKGROUND: Long-term survival of high-risk neuroblastoma patients is still below 50% despite intensive multimodal treatment. This trial aimed to address whether the addition of two topotecan-containing chemotherapy courses compared to standard induction therapy improves event-free survival (EFS) of these patients. PATIENTS AND METHODS: An open-label, multicenter, prospective randomized controlled trial was carried out at 58 hospitals in Germany and Switzerland. Patients aged 1-21 years with stage 4 neuroblastoma and patients aged 6 months to 21 years with MYCN-amplified tumors were eligible. The primary endpoint was EFS. Patients were randomly assigned to standard induction therapy with six chemotherapy courses or to experimental induction chemotherapy starting with two additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy (eight courses in total). After induction chemotherapy, all patients received high-dose chemotherapy with autologous hematopoietic stem cell rescue and isotretinoin for consolidation. Radiotherapy was applied to patients with active tumors at the end of induction chemotherapy. RESULTS: Of 536 patients enrolled in the trial, 422 were randomly assigned to the control arm (n = 211) and the experimental arm (n = 211); the median follow-up time was 3.32 years (interquartile range 1.65-5.92). At data lock, the 3-year EFS of experimental and control patients was 34% and 32% [95% confidence Interval (CI) 28% to 40% and 26% to 38%; P = 0.258], respectively. Similarly, the 3-year overall survival of the patients did not differ [54% and 48% (95% CI 46% to 62% and 40% to 56%), respectively; P = 0.558]. The response to induction chemotherapy was not different between the arms. The median number of non-fatal toxicities per patient was higher in the experimental group while the median number of toxicities per chemotherapy course was not different. CONCLUSION: While the burden for the patients was increased by prolonging the induction chemotherapy and the toxicity, the addition of two topotecan-containing chemotherapy courses did not improve the EFS of high-risk neuroblastoma patients and thus cannot be recommended. CLINICAL TRIALS. GOV NUMBER: NCT number 03042429.

Safety and efficacy of denosumab in children with osteogenesis imperfect--a first prospective trial.

OBJECTIVES: Osteogenesis imperfecta (OI) is a rare hereditary disease leading to bone fragility. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. Aim of this study was a 48-week, open-label, pilot study of the safety and efficacy of denosumab in 10 children with OI. METHODS: Ten patients (age range: 5.0-11.0 years; at least two years of prior bisphosphonate treatment) with genetically confirmed OI were studied. Denosumab was administered subcutaneously every 12 weeks with 1 mg/kg body weight. Primary endpoint was change of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 48 weeks. Safety was assessed by bone metabolism markers and adverse event reporting. RESULTS: Mean relative change of lumbar aBMD was +19 % (95%-CI: 7-31%). Lumbar spine aBMD Z-Scores increased from -2.23±2.03 (mean±SD) to -1.27±2.37 (p=0.0006). Mobility did not change (GMFM-88 +2.72±4.62% (p=0.16); one-minute walking test +11.00±15.82 m (p=0.15). No severe side effects occurred. CONCLUSIONS: On average, there was a significant increase in lumbar spine aBMD percent change after 48 weeks of denosumab. There was no change in mobility parameters and no serious adverse events. Further trials are necessary to assess long-term side effects and efficacy.

Early vibration assisted physiotherapy in toddlers with cerebral palsy - a randomized controlled pilot trial.

OBJECTIVES: to investigate feasibility, safety and efficacy of home-based side-alternating whole body vibration (sWBV) to improve motor function in toddlers with cerebral palsy (CP). METHODS: Randomized controlled trial including 24 toddlers with CP (mean age 19 months (SD±3.1); 13 boys). INTERVENTION: 14 weeks sWBV with ten 9-minute sessions weekly (non-individualized). Group A started with sWBV, followed by 14 weeks without; in group B this order was reversed. Feasibility (≥70% adherence) and adverse events were recorded; efficacy evaluated with the Gross Motor Function Measure (GMFM-66), Pediatric Evaluation of Disability Inventory (PEDI), at baseline (T0), 14 (T1) and 28 weeks (T2). RESULTS: Developmental change between T0 and T1 was similar in both groups; change scores in group A and B: GMFM-66 2.4 (SD±2.1) and 3.3 (SD±2.9) (p=0.412); PEDI mobility 8.4 (SD±6.6) and 3.5 (SD±9.2) (p=0.148), respectively. In two children muscle tone increased post-sWBV. 24 children received between 67 and 140 sWBV sessions, rate of completed sessions ranged from 48 to 100% and no dropouts were observed. CONCLUSION: A 14-week home-based sWBV intervention was feasible and safe in toddlers with CP, but was not associated with improvement in gross motor function.

Chronic relapsing opsoclonus-myoclonus syndrome: combination of cyclophosphamide and dexamethasone pulses.

Opsoclonus-myoclonus syndrome (OMS) is a rare and debilitating disorder of unknown etiology affecting children and adults. Outcome is unfavourable; approximately 80% of children with OMS suffer from mild to severe neurological handicaps, mainly cognitive impairment. A standard therapy does not exist. Due to the possible immune-mediated mechanisms, treatment with steroids, ACTH, plasmapheresis and immunoglobulins can be successful. However, some children become steroid dependent and symptoms may reoccur after treatment has been finished. We present two girls with OMS, who had a prolonged clinical course lasting 4 and 9 years with many relapses. Both children developed symptoms around the age of two years. Diagnostic work-up to exclude neuroblastoma was negative. Several treatment modalities including oral steroids, dexamethasone pulses, immunoglobulin and cyclosporine were used without lasting success. In addition, cognitive impairment developed in both children. In order to prevent further clinical and mental deterioration, 6 pulses of cyclophosphamide in combination with dexamethasone pulses every 4 weeks were administered. Both children showed significant improvement of OMS symptoms. One girl is still symptom free 18 months after treatment, mild ataxia developed in the other after 12 months. Both children are mentally handicapped and in special need schools. We conclude that combination of cyclophosphamide pulses and dexamethasone pulse therapy is a therapeutic option even after a long clinical course to improve symptoms of OMS.

[Procedure guidelines for MIBG-scintigraphy in children].

The German translation of the EANM guideline for MIBG scintigraphy in children (Olivier P et al. EJNM MI 2003; 30: B45-B50; Hahn K. Der Nuklearmediziner 2002; 25: 101-105) was reviewed and actualized according to current publications, legal requirements and conditions in Germany. For the first time this guideline was generated in consensus with the neuroblastoma study group of the Association of Paediatric Haematologie and Oncology (GPOH) with the result of an interdisciplinary recommendation. Further main alterations are related to the recommended (123)I activities with respect to the new EANM Paediatric Dosage Card and the explicit recommendation of SPECT.

[Dosimetry for therapeutic treatment of neuroblastoma by 131I-mIBG]. / Dosimetrie bei der Therapie von Neuroblastomen mit 131I-mIBG.

AIM: Targeted radiotherapies using iodine-131 meta-iodobenzylguanidin have long been in use for treatment of stage IV neuroblastoma but reliable dosimetric data are scarce. METHOD: This work presents an approach to determine the whole body exposure and tumour doses delivered during therapy. Dosimetric data are reported and discussed for six treatments carried out according to the trial protocol NB2004 as it is in use in our study in the last two years. RESULTS: Whole body exposures are found to be in the range of 1.75 to 2.5 Gy whereas tumour doses vary between 15 and 55 Gy. CONCLUSION: The course of action prescribed by the trial protocol allows whole body exposure as well as tumour doses to be determined routinely.

Is there a benefit of 131 I-MIBG therapy in the treatment of children with stage 4 neuroblastoma? A retrospective evaluation of The German Neuroblastoma Trial NB97 and implications for The German Neuroblastoma Trial NB2004.

AIM: (131)I-meta-iodobenzylguanidine ((131)I-MIBG) therapy has been used in neuroblastoma treatment for many years but its value in high intensive first line treatment protocols is not exactly known. PATIENTS, METHODS: Stage 4 neuroblastoma patients >1 year with (123)I-MIBG positive residual disease (primary tumour and/or metastasis) after complete induction chemotherapy according to the German neuroblastoma trial NB97 were retrospectively analyzed. RESULTS: One-hundred-eleven patients had (123)I-MIBG positive residual disease after complete induction chemotherapy. Forty patients received (131)I-MIBG therapy using a median activity of 0.44 GBq/kg body weight. By univariate analysis, patients who underwent (131)I-MIBG therapy had a better 3-year event free survival (3-y-EFS 46 +/- 8%) and 3-year overall survival (3-y-OS 58 +/- 9%) than 71 patients without (131)I-MIBG therapy (3-y-EFS 19 +/- 5%, p = 0.003; 3-y-OS 43 +/- 6%, p = 0.037). However, subgroup analysis of 66 patients who underwent high dose chemotherapy with autologous stem cell transplantation (ASCT) during treatment found a very similar outcome with (131)I-MIBG therapy (3-y-EFS 49 +/- 9%, 3-y-OS 59 +/- 10%) and without (131)I-MIBG therapy (3-y-EFS 33 +/- 9%, p = 0.171; 3-y-OS 59 +/- 9%, p = 0.285) due to the dominating effect of ASCT. By multivariate analysis, (131)I-MIBG therapy had no impact on EFS (p = 0.494) and OS (p = 0.891). Only ASCT, external beam radiation therapy and MYCN amplification were important for EFS and OS. CONCLUSIONS: An independent advantage of I-131-MIBG therapy could not be proven in this retrospective analysis. The ongoing German Neuroblastoma Trial NB2004 will address the influence of (131)I-MIBG therapy with emphasis on tumour dosimetry.

A lack of neuroblastoma in Down syndrome: a study from 11 European countries.

An epidemiological investigation in 11 European countries comprising a total childhood population of 54.1 million children and using 8 separate data sources was conducted to evaluate the occurrence of neuroblastoma in Down syndrome (DS). No cases of DS were detected among 6724 infants and children with neuroblastoma, although more than five were expected. This highly significant result (P = 0.0045 according to the Poisson test) is consistent with data in the literature, which contains only two poorly detailed cases in epidemiological studies and one ganglioneuroma in a DS mosaic patient. Like other tumors, such as leukemias, testicular germ cell tumors and lymphomas are in excess in DS patients; the lack of neuroblastomas does not reflect a general decreased incidence of cancer but rather a specific underrepresentation of this precise tumor. S-100 b protein, the gene for which maps to the long arm of chromosome 21, (a) is overproduced in DS patients, (b) produces growth inhibition and differentiation of neural cells in vitro, (c) is abundant in good-prognosis neuroblastomas, and (d) has been shown to induce growth inhibition and differentiation and cell death in several human and murine neuroblastoma cell lines and could be responsible for this variation. Additional epidemiological and experimental studies are warranted to confirm our interpretation of these data.

Which cases are found and missed by neuroblastoma screening at 1 year? Results from the 1992 to 1995 study in three Federal States of Germany.

PURPOSE: Neuroblastoma screening during the first half-year of life is associated with a two- to three-fold overdiagnosis. Because regression processes seem to be confined to infancy, we investigated whether screening at 1 year would be associated with fewer overdiagnoses, and we investigated the characteristics of thus-detected and not-detected patients. PATIENTS AND METHODS: Thin-layer chromatography was used for semiquantitative assessment of urine samples dried on filter paper and obtained when patients were 10 to 14 months old (sample 1) and 17 to 19 months old (sample 2). Abnormal results were reanalyzed quantitatively from the same specimen by high-performance liquid chromatography and/or gas chromatography-mass spectrometry. RESULTS: A total of 200,054 children of the German federal states Lower Saxony, Northern Rhine-Westphalia, and Bremen were screened from May 1992 to April 1995. Of 229,078 investigated samples (100%), 228,245 (99.6%) were first, 657 (0.3%) were second, and 176 (0.08%) were third urine specimens. The compliance rate was 27.8%, but it continued to increase throughout the study period and in the last year it was 43. 3%. The second screening offered at 18 months was accepted by only 12.1% (24,259) of the children. Thirty children underwent clinical examination, and nine asymptomatic neuroblastoma cases were detected (stage 1, n = 4; stage 2, n = 2; stage 3, n = 2; stage 4, n = 1; detection rate, 1:22,228). The results of 21 tests were false-positive. Ten children with false-negative test results presented 8 to 35 months later with neuroblastoma (stage 1 tumor, n = 1; stage 2, n = 1; stage 3, n = 1; stage 4, n = 7; five of nine tumors were N-myc-amplified tumors). Three children were nonsecretors at the time of diagnosis. Fifty-two patients were "missed" (not screened), and 37 children developed neuroblastoma before the age of screening (early cases). During the same period, a total of 23.6 cases per million children within the screening area and 24.0 cases per million children outside the screening area were diagnosed as neuroblastoma cases (not significant [NS]). In prescreening times in the area of the later screening states, 20.7 cases per million children were found (NS). CONCLUSION: Screening at 1 year of age demonstrated a lower detection rate than earlier screening programs and did not produce a "halo effect." The good prognostic features of early-detected cases and the poor characteristics of not-detected-but-late-presenting cases corresponded to those of the related age groups.

Telomerase activity and telomerase subunits gene expression patterns in neuroblastoma: a molecular and immunohistochemical study establishing prognostic tools for fresh-frozen and paraffin-embedded tissues.

PURPOSE: We have recently demonstrated that telomerase activity (TA) is an independent prognostic factor in neuroblastomas. In the present study, the prognostic impact of TA and gene expression of the three major telomerase subunits is evaluated by molecular and immunohistochemical techniques in fresh-frozen and paraffin-embedded tissues. PATIENTS AND METHODS: One hundred thirty-three neuroblastomas of all stages were analyzed for TA. The TA levels of 75 neuroblastoma cases were correlated with gene expression of telomerase subunits hTRT, human telomerase RNA (hTR), and telomerase protein 1 (TP1) by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), using an innovative approach on the LightCycler instrument (Roche Diagnostics, Mannheim, Germany). For selected cases, the applicability of RT-PCR and immunohistochemistry for hTRT expression analysis was investigated in paraffin-embedded tissues. TA and subunit expression patterns were correlated with traditional prognostic indicators and disease outcome. RESULTS: TA was present in a total of 39 (29.3%) of 133 neuroblastomas and in 31 (29.8%) of 104 initial neuroblastomas without cytotoxic pretreatment. TA was significantly correlated with both event-free and overall survival (P <.0001). Furthermore, we found a significant correlation between expression levels of TA and hTRT (P <.0001) as well as hTR (P <.001). Multivariate analysis revealed only TA and tumor stage but not serum lactate dehydrogenase, MYCN amplification, or age at diagnosis as independent prognostic factors. CONCLUSION: The significant correlation with clinical outcome strongly recommends that analysis of TA be incorporated into the clinical investigation of each individual neuroblastoma at the time of diagnosis. Because the mere presence or absence of TA without further quantification is sufficient basis for predicting disease outcome, the telomeric repeat amplification protocol assay could be complemented with but not replaced by analysis of hTRT or hTR expression.

MYCN-status in neuroblastoma: characteristics of tumours showing amplification, gain, and non-amplification.

While the role of MYCN-amplification (MNA) for risk assessment in neuroblastoma is undisputed, the phenomenon of gene copy excess below the amplification threshold is rarely described. To discuss biological characteristics and the clinical impact of the so-called MYCN-gain versus amplified or non-amplified cases, we investigated the MYCN status of 659 patients uniformly analysed by fluorescence in situ hybridisation. The number of MYCN-amplified tumours in our cohort was 18% (116/659); an additional 38 tumours (6%) displayed MYCN-gain. Both alterations were associated with an advanced stage disease, an increased patient age and further chromosomal alterations. Most of the amplified neuroblastomas displayed 1p aberrations, whereas MYCN-gain tumours correlated with 11q alterations. In contrast to the amplified cases, tumours with gain displayed no increased MYCN RNA levels. MNA versus non-amplification discriminated between good and poor outcomes, independent of stage, age and the degree of amplification. However, patients with amplified tumours showed a significantly better outcome when this was combined with non-stage 4 disease and age <1 year versus stage 4 and age < 1 year. Although MYCN-gain was associated with poor event-free-survival (EFS) in stages 1-3, 4S (P=0.005), this might be related to associated genetic aberrations and not to the MYCN-gain itself. A survival difference between neuroblastomas with gain and single copy MYCN could not be delineated. In conclusion, MNA predicts a poor outcome for neuroblastoma patients of all stages and age. MYCN-gain is also a characteristic feature of advanced stage tumours and older patients, but is not associated with higher MYCN expression and appears not to be discriminative in predicting patient outcome.

Tumour markers are poor predictors for relapse or progression in neuroblastoma.

The value of the tumour markers vanillylmandelic acid (VMA) and homovanillic acid (HVA) in urine (u) and serum (s), neurone-specific enolase (NSE), and lactate dehydrogenase (LDH) in the early prediction of relapse/progression in neuroblastoma is not known. We analysed the data of neuroblastoma patients who had successfully completed first-line treatment and had laboratory results available from their initial diagnosis and from relapse/progression (n=196). Patients' overall survival from relapse or progression was 21.5+/-4.2% (mean+/-standard deviation). At diagnosis, we found abnormal results in 75% for VMA and/or HVA (s), 92% for VMA and/or HVA (u), 90% for NSE, and 81% for LDH. We found a lower incidence of abnormal results at relapse or progression with 40% for VMA and/or HVA (s), 54% for HVA and/or VMA (u), 61% for NSE, and 48% for LDH. Sensitivity of all markers was higher for metastatic compared with local recurrence. NSE was the best, being able to detect 42% of the localised relapses, 77% of the combined local/metastatic relapses, and 69% of the metastatic recurrences. Relapse or progression in neuroblastoma cannot be detected reliably by monitoring tumour markers alone. Therefore, follow-up of neuroblastoma patients must include clinical assessment and imaging studies.

Comparison of DNA aneuploidy, chromosome 1 abnormalities, MYCN amplification and CD44 expression as prognostic factors in neuroblastoma.

A comparison of the prognostic impact of five molecular variables in a large series was made, including tests of their nonrandom association and multivariate analysis. Molecular data were available for 377 patients and MYCN amplification, cytogenetic chromosome 1p deletion, loss of chromosome 1p heterozygosity, DNA ploidy and CD44 expression were investigated. Their interdependence and influence on event-free survival was tested uni- and multivariately using Pearson's chi 2-test, Kaplan-Meier estimates, log rank tests and the Cox's regression model. MYCN amplification was present in 18% (58/322) of cases and predicted poorer prognosis in localised (P < 0.001), metastatic (P = 0.002) and even 4S (P = 0.040) disease. CD44 expression was found in 86% (127/148) of cases, and was a marker for favourable outcome in patients with neuroblastoma stages 1-3 (P = 0.003) and 4 (P = 0.017). Chromosome 1p deletion was cytogenetically detected in 51% (28/55), and indicated reduced event-free survival in localised neuroblastoma (P = 0.020). DNA ploidy and loss of heterozygosity on chromosome 1p were of less prognostic value. Most factors of prognostic significance were associated with each other. By multivariate analysis, MYCN was selected as the only relevant factor. Risk estimation of high discriminating power is, therefore, possible for patients with localised and metastatic neuroblastoma using stage and MYCN.

Treatment of neuroblastoma stage 4 with 131I-meta-iodo-benzylguanidine, high-dose chemotherapy and immunotherapy. A pilot study.

Disseminated neuroblastoma after infancy has a prognosis of approximately 10-20% with conventional therapy. We investigated the role of high-dose chemotherapy (HDCT) with peripheral blood stem cell (PBSC) rescue in combination with 131I-metaiodobenzylguanidine ([131I-m]IBG). 11 children with neuroblastoma stage 4 were pretreated within the German Neuroblastoma Trial NB90 and included in a high-dose concept for consolidation. Remission was documented by ultrasound, CT, NMR, or [123I-m]IBG scanning. HDCT was a combination of melphalan (180 mg/m2), carboplatin (1,500 mg/m2) and etoposide (40 mg/kg). All children were treated by [131I-m]IBG (0.58 GBq/kg) prior to high-dose treatment. All 11 children were additionally treated with antiGD2 murine- or chimeric-antibody (ch14.18). 4 children had no change to their remission status but three achieved a complete response (from a partial response to first line) and one a partial response (from no response to first line). The other 3 children progressed, 2 dying of their disease. Using Kaplan-Meier analysis, the probability of progression-free survival was 0.70 +/- 0.15 with a median observation time of 19 months. 9/11 children are alive, 8 without progression or relapse, whilst 2 have died of their disease. The combination of mIBG plus high-dose chemotherapy with PBSC support supplemented by immunotherapy with antiGD2 antibody appears to be a feasible and effective treatment regimen for disseminated neuroblastoma in this limited series. Larger numbers of patients should be treated to confirm these results.

The current contribution of molecular factors to risk estimation in neuroblastoma patients.

The association of molecular characteristics with prognosis has been reported, but not their relationship with each other and their impact in the context of known clinical risk factors. In this study, data of 1249 consecutive intent-to-treat-neuroblastoma patients with more than 1 year follow-up were examined by multivariate analysis using loglinear and Cox proportional hazard regression models on a stage-related basis (stages 1-3: 600, 4S: 116, 4: 533). In a first step, risk factors were identified from 18 selected clinical variables, and risk groups defined. The second step investigated whether molecular characteristics (MYCN, LOH 1p, del 1p, CD44, N-ras, NGF-R, bcl-2, APO-1 (CD95)) contributed additional prognostic information to the model. The loglinear model demonstrated several interactions between clinical factors. By the Cox regression model, seven independent clinical risk factors were found for stages 1-3, seven for stage 4 and two for stage 4S. By subsequent introduction of all molecular variables, MYCN amplification only added significant prognostic information to the clinical factors in localised and stage 4 neuroblastoma. The models allowed the definition of risk groups for stages 1-3 patients by age (e beta = 5.09) and MYCN (e beta = 4.26), for stage 4 by MYCN (e beta = 2.78) and number of symptoms (e beta = 2.44) and for stage 4S by platelet count (e beta = 3.91) and general condition (e beta = 2.99). Molecular factors and in particular MYCN contribute significantly to risk estimation. In conjunction with clinical factors, they are powerful tools to define risk groups in neuroblastoma.

10 years' neuroblastoma screening in Europe: preliminary results of a clinical and biological review from the Study Group for Evaluation of Neuroblastoma Screening in Europe (SENSE).

Between January 1986 and May 1996, 870,313 children were tested in European neuroblastoma (NB) screening programmes. Among these children, 82 cases of NB (age range 4-24 months, median 11 months) were detected by screening. 83% of the patients had localised NB and 17% were diagnosed with generalised NB (stage 4, 10%; stage 4s, 7%). Unfavourable biological markers (MYCN amplification, loss of heterozygosity (LOH) 1p36, DNA di/tetraploidy) were observed in 14% of 76 biologically examined cases. The median follow-up time of all the patients was 21.5 months (range 1-101 months). To date, 69 patients are in complete remission (CR) and 2 patients have died due to therapy (stage 4, 1 patient; stage 3, 1 patient with unfavourable markers). Apart from screened patients, 16 other patients with NB were found who had previously had a normal screening test, i.e. 'false negative' patients (age range 10-41 months, median 31.5 months). The median interval between screening and diagnosis was 24.5 months (range 6-35 months). 11 of the 'false negative' patients suffered from generalised NB (stage 4) and 5 had localised NB at diagnosis. Unfavourable biological markers were observed in 7/12 patients. 5 patients have died, 2 achieved partial remission and 9 CR. 9 of the 11 patients with unfavourable biological markers diagnosed due to NB screening are currently in CR. It is very likely that, among the patients without unfavourable biological markers, we detected tumours which may have regressed spontaneously. These children may have undergone 'unnecessary,' but unavoidable, diagnostic procedures and therapy. To reduce the number of 'false negative' patients, a later screening could be helpful and should be evaluated.

Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age.

During the last two decades new diagnostic and therapeutic tools have been utilized to improve the poor survival chances of children with stage 4 neuroblastoma. This study reviews the risk profiles and the long-term outcome of patients from five consecutive German neuroblastoma trials. A total of 96% of all German patients registered at the German childhood cancer registry with neuroblastoma stage 4 over 1 year of age at diagnosis entered one of the trials during 1979-2001. Eight hundred and twenty-eight consecutive children were analyzed retrospectively. In spite of having significantly improved diagnostic tools like bone marrow superstaging and mIBG scintigraphy the stage 4 incidence did not increase after reaching completeness of the registry (5.4 cases/100,000 children at 1-14 years of age; P=0.52). The distribution of the primary tumors and of metastases was constant over the periods. The amount of bone marrow infiltration did not change with time. The risk factors lactate dehydrogenase, ferritin and MYCN, and the clinical risk groups 4A, 4B, 4C also remained constant over the trials with a few exceptions for NB97. The 5-year event free survival increased from 0.01+/-0.01 (NB79) to 0.14+/-0.03 (NB85), 0.16+/-0.04 (NB82), 0.27+/-0.02 (NB90), and 0.33+/-0.04 (NB97). The overall survival rates improved similarly from 0.04 (NB79) to 0.44 (NB97). In conclusion, the improved survival was associated with better treatment and not caused by lower risk profiles in stage 4 neuroblastoma patients.

Neuroblastoma: current drug therapy recommendations as part of the total treatment approach.

Neuroblastoma represents one of the most challenging malignancies for treatment decisions because of its unusual biological behaviour. The features include spontaneous regression (regressive type), maturation to ganglioneuroma (maturative type) and largely treatment-resistant progression (progressive type). Current knowledge allows only partial prediction of type. For practical reasons, patients may be categorised as an 'observation', a 'standard risk' or a 'high risk' treatment arm. During the last 2 decades, 5-year survival rates for children with neuroblastoma have increased from 48 to 67%. The main achievements were the reduction of chemotherapy in patients with localised disease and the increased efficacy of chemotherapy in metastatic neuroblastoma stage 4 (5-year survival increased from 8 to 33%). Different goals for chemotherapy (e.g. stopping rapid progression, improvement of symptoms, induction and maintenance of remission) require different dosages and durations of treatment (range 1 week to 9 months). The main risks of chemotherapy are toxic death (rate up to 15%) predominantly during the periods of bone marrow depression and the development of secondary leukaemias (up to 7% cumulative risk after 4 years). In conclusion, the use of cytotoxic drugs can be completely omitted in a substantial proportion of low risk patients with neuroblastoma. On the other hand, for high risk patients with the disease, intensive polychemotherapy represents the basis and the backbone of treatment among other modalities.

Isolation and transplantation of highly purified autologous peripheral CD34(+) progenitor cells: purging efficacy, hematopoietic reconstitution and long-term outcome in children with high-risk neuroblastoma.

We have investigated the purging efficacy of positive selection of autologous mobilized CD34(+) peripheral stem cells in 22 children with high-risk neuroblastoma. CD34(+) cell selection was performed using the method of magnetic-activated cell sorting (MACS). The median purity of the CD34(+) cells post selection was 97.6% (range 81.7-99.7). For detection of contaminating neuroblastoma cells before and after CD34(+) selection, the chimeric anti-disialoganglioside GD2 antibody delta ch 14.18 was used. Prior to positive selection, various numbers of contaminating neuroblastoma cells were found in 17 patients. After positive CD34(+) cell selection, low numbers of neuroblastoma cells were only detectable in four patients. In 18 patients, high-dose chemotherapy was performed and the isolated CD34(+) cells were reinfused. In all patients, a rapid neutrophil recovery was seen with a median time to reach 0.5 x 10(9)/l neutrophils of 12 days (range 8-24 days). Nine of the 18 patients are free of progression with a median follow-up of 55 months (range 45-70 months). Two patients are alive with relapse, six patients died due to progression or relapse and one patient died due to secondary AML 10 months after transplant while in remission from neuroblastoma. In summary, we show that, through a highly effective positive selection method, a high purging efficacy can be obtained without compromising the hematopoietic reconstitution capacity of the graft.

High-dose chemotherapy with autologous stem cell rescue in children with nephroblastoma.

Children with Wilms tumor who have a particular risk of failure at relapse or at primary diagnosis were treated with high-dose chemotherapy (HDC) and autologous peripheral blood stem cell rescue in order to improve their probability of survival. From April 1992 to December 1998, 23 evaluable patients received HDC within the German Cooperative Wilms Tumor Studies. Nineteen were given melphalan, etoposide and carboplatin (MEC); the others received different regimens. The dose of carboplatin was adjusted according to renal function. Indications for HDC were high-risk relapse in 20 patients, bone metastases in two patients and no response in one patient. Fourteen of 23 patients are alive after a median observation time of 41 months, 11 of 14 in continuous complete remission, three in CR after relapse post HDC. The estimated survival and event-free survival for these patients are 60.9% and 48.2%. Twelve children relapsed after HDC; nine of them died within 12 months and three are surviving from 20 to 33 months after relapse. The main toxicities were hematologic, mucositis and renal (tubular dysfunction; intermittent hemodialysis in one patient). There were no toxic deaths. About half of the children suffering from Wilms tumor with very unfavorable prognostic factors survive disease-free after HDC for over 3 years. Besides hematological toxicity, mucositis and infections, renal function is at risk during HDC. With dose adjustment on glomerular filtration rate, however, no permanent renal failure was observed.