Survey on paediatric tumour boards in Europe: current situation and results from the ExPo-r-Net project

Background

Under the ExPO-r-NeT project (European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment), we aimed to identify paediatric oncology tumour boards in Europe to investigate the kind of technologies and logistics that are in place in different countries and to explore current differences between regions.

Methods

A 20-question survey regarding several features of tumor boards was designed. Data collected included infrastructure, organization, and clinical decision-making information from the centres. The survey was distributed to the National Paediatric Haematology and Oncology Societies that forwarded the survey to the sites. For comparative analysis, respondents were grouped into four geographical regions.

Results

The questionnaire was distributed amongst 30 countries. Response was obtained from 23 (77%) that altogether have 212 paediatric oncology treating centres. A total of 121 institutions answered (57%). Ninety-one percent of the centres hold multidisciplinary boards; however, international second consultations are performed in 36% and only 15% participate on virtual tumor boards. Videoconferencing facilities and standard operational procedures (SOPs) are available in 49 and 43% of the centres, respectively. There were statistically significant differences between European regions concerning meeting infrastructure and organization/logistics: specific room, projecting equipment, access to medical records, videoconferencing facilities, and existence of SOPs.

Conclusion

Paediatric tumor boards are a common feature in Europe. To reduce inequalities and have equal access to healthcare, a virtual network is needed. Important differences on the functioning and access to technology between regions in Europe have been observed and need to be addressed.

     

Anti-neuroblastoma effect of ch14.18 antibody produced in CHO cells is mediated by NK-cells in mice

Successful treatment of stage 4 neuroblastoma remains a major challenge in pediatric oncology. In order to improve the outcome, passive immunotherapy using human-mouse chimeric monoclonal anti-disialoganglioside GD2 antibody ch14.18 has been evaluated in early phase clinical trials with promising results in progressing stage 4 neuroblastoma patients. In preparation of European phase III clinical trial (HR-NBL-1/ESIOP), the cell line used for production of ch14.18 was changed. Specifically, the plasmid encoding for ch14.18 antibody was recloned into CHO cells. Here, we report the in vitro and in vivo anti-neuroblastoma activity of antibody ch14.18 produced in CHO cells (ch14.18/CHO) compared to that of ch14.18 manufactured from SP2/0 (ch14.18/SP2/0) and NS0 cells (ch14.18/NS0). First, we demonstrate identical binding of ch14.18/CHO to the nominal antigen disialoganglioside GD2 in vitro compared to ch14.18/SP2/0 and ch14.18/NS0. Binding was GD2-specific, since all precursor- and metabolite-gangliosides of GD2 tested were not recognized by ch14.18/CHO. Second, the functional properties of ch14.18/CHO were determined in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) reactions against GD2 positive neuroectodermal tumor cell lines in vitro. There was no difference in CDC mediated specific tumor cell lysis among the three different ch14.18 antibody preparations. Interestingly, ch14.18/CHO showed superior ADCC activity at low antibody concentrations. Third, the efficacy of ch14.18/CHO was evaluated in the NXS2 neuroblastoma model in vivo. Importantly, the ch14.18/CHO preparation was effective in suppression of experimental liver metastasis in this model. In vivo depletion of NK-cells completely abrogated this effect, suggesting that the mechanism involved in the ch14.18/CHO induced anti-neuroblastoma effect is mediated by NK-dependent ADCC.     

Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients

BACKGROUND: Urinary catecholamine metabolites are well-known to be elevated in patients with neuroblastoma. Some investigators have described different patterns in favorable and unfavorable cases. However, extended studies have not been published. PROCEDURE: We investigated urinary catecholamine patterns and their correlation to stage, biological features, and outcome in 114 consecutively clinically diagnosed neuroblastoma patients. RESULTS: Sensitivity of vanillylmandelic acid (VMA), homovanillic acid (HVA), and dopamine (DA) was 80.7, 71.9, and 61.3%, respectively. In 91.2% of patients at least one parameter was above normal. High VMA levels were associated with favorable biological features, high DA levels were predominantly found in biologically unfavorable disease. Whereas patients with normal HVA levels had a significant better outcome, the other parameters showed no significant association with prognosis. For disseminated neuroblastoma of infancy, DA/VMA ratio proved to be helpful for the discrimination of stage 4 versus stage 4s. CONCLUSION: Urinary catecholamines appear to be useful to give a first but important hint about the biological behavior and thus the prognosis of the underlying disease. Particularly DA/VMA ratio may serve as a tool for "biological grading"-especially in disseminated disease of infancy. In addition, it may be speculated that HVA negativity and low DA/VMA ratio may be helpful for the decision of a "wait and see" strategy in selected neuroblastoma patients with localized disease.     

Treatment for soft tissue sarcoma in childhood and adolescence

Summary OBJECTIVE: The aim of the CWS 96 Study was to achieve an optimal treatment in children and adolescents with soft tissue sarcoma (STS) implementing a further refinement of risk-adapted allocation to chemotherapy, surgery and radiotherapy. METHODS: Treatment stratification was based on tumour histology, TNM status, postsurgical stage, localisation and age. Local tumour control was ensured by surgery and risk-adapted radiotherapy. RESULTS: From 1995 to 2002, 89 patients were registered in Austria. The 3-year event-free survival (EFS) and overall survival rates (OS) were 63% ± 6% and 71% ± 6%, respectively. 59/89 patients had localised RMS-like (rhabdomayosarcoma) STS (EFS 73% ± 7%), 14 had localised Non-RMS STS (EFS, 54% ± 16%) and 15 patients had metastatic disease at diagnosis (EFS, 33% ± 12%), 1 patient had fibromatosis. The EFS rates at 3 years in patients with localised RMS-like tumours according to risk group were 92% ± 8% for low and standard risk (12 patients) and 67% ± 8% for high risk (47 patients). Favourable primary tumour sites of nonmetastatic RMS-like STS i.e. orbit, head/neck nonparameningeal or genitourinary non-bladder/prostate were diagnosed in 15 patients (1 of 15 patients died). In 44 patients with unfavourable localisation such as parameningeal, genitourinary bladder/prostate, extremity and others, 7 deceased. The 3-year EFS according to histology in patients with RMS-like STS was 61% ± 11% for RME (embryonal RMS ) (28 patients) and 71% ± 15% for RMA (alveolar RMS) (10 patients). The most common treatment failure was local relapse occurring in 21% of patients in the high-risk group. CONCLUSION: Risk-adapted individualisation of treatment led to a reduction of chemotherapy in the low- and standard-risk group without compromising survival. The outcome of RME and RMA was similar in this cohort of patients. These preliminary results after a median observation time of 2.5 years confirm the CWS 96 strategy.

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Die Behandlung von Weichteilsarkomen bei Kindern und JugendlichenErgebnisse der CWS-96-Studie – Österreich

Zusammenfassung ZIEL: Die CWS-96-Studie für Behandlung von Weichteilsarkomen (WS) im Kindes- und Jugendalter verfolgte eine maximale Tumorkontrolle bei Minimierung von Spätfolgen durch eine verbesserte risikoadaptierte Chemo-, Operations- und Radiotherapie. METHODEN: Die Stratifikation der Patienten erfolgte nach Histologie, TNM-Status, postchirurgischem Stadium, Lokalisation und Alter. Die Lokalkontrolle wurde durch Chirurgie und risikoadaptierte Bestrahlung angestrebt. ERGEBNISSE: Im Zeitraum von 1995 bis 2002 wurden 89 Patienten registriert. Das ereignisfreie (EFS) und das absolute Überleben (OS) nach 3 Jahren lag bei 63% ± 6% bzw. 71% ± 6%. 59 von 89 Patienten hatten lokalisierte RMS-(Rhabdomysoarkom-)artige WS (EFS, 73% ± 7%), 14 lokalisierte Non-RMS-artige WS (EFS, 54% ± 16%), 15 initial disseminierte WS (EFS, 33% ± 12%) und 1 Fibromatose. Das 3-Jahres-Überleben bei lokalisierten RMS-artigen nach Risikogruppe ergab 92% ± 8% EFS für niedriges und Standard-Risiko (12 Patienten), sowie 67% ± 8% EFS für hohes Risiko (47 Patienten). Die Lokalisation der 59 nicht metastasierten RMS-artigen WS war bei 15 Patienten in als günstig definierten Regionen (Orbita, Kopf/Hals – nicht parameningeal oder urogenital – nicht Blase/Prostata: 1 von 15 Patienten verstorben), während bei 44 Patienten ungünstige Lokalisationen vorlagen (Kopf/Hals – parameningeal, urogenital – Blase/Prostata, Extremitäten und andere: 7 von 44 Patienten verstorben). Das EFS nach Histologie in der Kategorie der lokalisierten RMS-artigen lag für embryonale RMS (RME) (28 Patienten) bei 61% ± 11% und für alveoläre RMS (RMA) (10 Patienten) bei 71% ± 15%. Das Hauptproblem war das lokale Rezidiv, das bei 21% aller Patienten im Hochrisikoarm auftrat. SCHLUSSFOLGERUNG: Die risikoadaptierte Individualisierung der Therapie als oberstes Ziel führte zu Einsparungen an Chemotherapie in der Niedrig- und Standard-Risiko-Gruppe bei erhaltener guter Prognose. In dieser Patientenkohorte war das Überleben für RME und RMA ähnlich. Nach einer medianen Beobachtungszeit von 2,5 Jahren bestätigen diese ersten Ergebnisse die erfolgreiche Umsetzung des CWS-Konzeptes.

     

Changes over three decades in outcome and the prognostic influence of age-at-diagnosis in young patients with neuroblastoma: a report from the International Neuroblastoma Risk Group Project

Purpose

Increasing age has been an adverse risk factor in children with neuroblastoma (NB) since the 1970’s, with a 12-month age-at-diagnosis cut-off for treatment stratification. Over the last 30 years, treatment intensity for children >12 months with advanced-stage disease has increased; to investigate if this strategy has improved outcome and/or reduced the prognostic influence of age, we analysed the International Neuroblastoma Risk Group (INRG) database.

Patients and methods

Data from 11,037 children with NB (1974-2002) from Australia, Europe, Japan, North America. Cox modelling of event-free survival (EFS) tested if the era and prognostic significance of age-of-diagnosis, adjusted for bone marrow (BM) metastases and MYCN status, effects on outcome had changed.

Results

Outcome improved over time: 3-year EFS 46% (1974-1989) and 71% (1997-2002). The risk for those >18 months against ?12 decreased: hazard ratio (HR); 4.61 and 3.94. For age 13-18 months, EFS increased from 42% to 77%. Outcome was worse if: >18 months (HR 4.47); BM metastases (HR 4.00); and MYCN amplified (HR 3.97). For 1997-2002, the EFS for >18 months with BM involvement and MYCN amplification was 18%, but 89% for 0-12 months with neither BM involvement nor MYCN amplification.

Conclusions

There is clear evidence for improving outcomes for children with NB over calendar time. The adverse influence of increasing age-at-diagnosis has declined but it remains a powerful indicator of unfavourable prognosis. These results support the age-of-diagnosis cut-off of greater than 18 months as a risk criterion in the INRG classification system.