Introduction
ECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, ...observational studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation.
Methods
The platform’s database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted.
Results
ECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months.
Discussion
ECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past.
Pseudoacalasia como presentación de un tumor pediátrico Cortés Hernández, Marta; García Hidalgo, Laura; Escobosa Sánchez, Olga ...
Anales de pediatría,
March 2022, 2022-03-00, 2022-03-01, Letnik:
96, Številka:
3
Journal Article
Summary Background Before this study started, the standard postoperative chemotherapy regimen for stage II–III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, ...avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II–III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. Methods For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II–III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m2 at weeks 1–8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 μg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m2 given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants. Findings Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8–79·8). 2 year event-free survival was 92·6% (95% CI 89·6–95·7) for treatment including doxorubicin and 88·2% (84·5–92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4–9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3–98·8) for treatment including doxorubicin and 95·8% (93·3–98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence. Interpretation Doxorubicin does not need to be included in treatment of stage II–III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification. Funding See Acknowledgments for funders.
Atypical teratoid rhabdoid tumors (AT/RT) of the central nervous system are rare, very aggressive embryological tumors, typically diagnosed in young patients and having a low survival rate after ...diagnosis. The aim of this study was to emphasize, based on the latest results in the literature, the need for protocols for multidisciplinary treatment in these patients.
We report our series of 3 cases treated, diagnosed and followed up between 2009 and 2014. They were treated with multimodal therapy protocols (Rhabdoid SIOP-2007 and European Rhabdoid Registry EU-RHAB-2010). In addition, we carried out a literature review.
Two of our 3 cases (supratentorial and spinal tumors) did not show any progression of the disease after long follow-up, in contrast with most of the cases available in the literature. The second patient had a shorter survival.
Patient age at the time of diagnosis, supratentorial location of the mass and fewer complications with adjuvant treatments seem to be factors yielding good prognosis for AT/RT tumors. In agreement with the latest international protocols, multidisciplinary treatment is the ideal treatment, consisting of radiotherapy and chemotherapy after complete tumor resection.
Severe combined immunodeficiency is an inherited disease with profoundly defective T cells, B cells, and natural killer cells. X-linked severe combined immunodeficiency is the most common form. In ...this report, we describe a 4-month-old male infant who was admitted to our hospital with progressive breathlessness and abdominal mass. He was diagnosed with hepatoblastoma and presented a pneumocystis jirovecii pneumonia at the beginning of chemotherapy. Definitive diagnosis of X-linked severe combined immunodeficiency was established by DNA analysis of the interleukin 2 receptor gamma chain gene. This case is the first report which describes an X-linked severe combined immunodeficiency patient with hepatoblastoma.
Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find therapeutic leads for this ...subgroup, we analyzed 58 blastemal type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large replication cohort. Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (18.2% of blastemal cases); mutations in DICER1 and DIS3L2; and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations strongly altered miRNA expression patterns in tumors, which was functionally validated in cell lines expressing mutant DROSHA.
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•SIX1/2 mutations in blastemal type Wilms tumors induce a proliferation signature•DROSHA/DGCR8 microprocessor mutations lead to a broad decrease in miRNA processing•TP53 mutations are associated with aneuploidy, chromothripsis, and high lethality•IGF2 and MYCN/FBXW7 alterations are frequent in blastemal type tumors
Blastemal type Wilms tumors are associated with poor prognosis. Wegert et al. identify recurrent mutations in SIX1 and SIX2 that correlate with high proliferation and in DROSHA and DGCR8 that affect miRNA biogenesis, as well as a high frequency of IGF2 overexpression in these tumors.
Resumen Introducción El cáncer es la primera causa de muerte por enfermedad entre el primer año de vida y la adolescencia. Algunos tipos de enfermedad siguen constituyendo un reto en términos de ...curación. Existe por tanto una necesidad imperiosa de nuevos fármacos. Algunos descubrimientos recientes en la biología del cáncer abren la puerta al desarrollo de terapias dirigidas contra alteraciones moleculares concretas e inmunoterapia. Esto se ha traducido en resultados prometedores sobre todo en oncología de adultos, y en menor medida todavía en niños. Presentamos la actividad en ensayos clínicos precoces (fase i - ii ) en oncología pediátrica en España. Material y métodos A través de la Sociedad Española de Oncología y Hematología Pediátrica (SEHOP) contactamos a sus miembros para identificar los ensayos fase i - ii en cáncer pediátrico abiertos entre 2005 y 2015. Resultados En este periodo se abrieron 30 ensayos: 21 (70%) en tumores sólidos y 9 (30%) en hemopatías malignas y se incluyó a 212 pacientes. La mayoría están promovidos por la industria farmacéutica (53%). Desde 2010, 4 centros se han integrado en el consorcio internacional ITCC cuyo objetivo es desarrollar nuevas terapias en cáncer infantil. Esto ha permitido ampliar el abanico de posibilidades terapéuticas. Los resultados de ensayos clínicos terminados muestran la contribución de los investigadores españoles, la introducción de terapias dirigidas y sus beneficios. Conclusiones La actividad en ensayos clínicos precoces ha aumentado en estos años. La SEHOP está comprometida a desarrollar y participar en ensayos clínicos académicos colaborativos, que favorezcan el avance en las terapias frente al cáncer infantil.
The impact of biopsying Wilms tumour (WT) at diagnosis on assigning the tumour stage and recommended treatment remains controversial. To address this important question, we analysed the potential ...association of all types of biopsy with local recurrence in patients treated in the SIOP WT 2001 trial, where needle biopsy was permitted without ‘upstaging’ the tumour to stage III. Only open biopsy required treatment as stage III.
Among 2971 patients with unilateral WT (stages I-IV), 420 relapsed (139 local). Risk factors for recurrence were analysed by Cox proportional hazard methods.
Biopsy was performed in 969 of 2971 (33%) patients (64% cutting needle, 30% fine needle aspiration FNA and 6% open biopsy). Biopsied patients were older, with larger tumours and a greater proportion with high-risk histology. In multivariate analysis that included all factors associated with local recurrence in univariate analysis, only high-risk histology (hazard ratio HR = 2.32; 95% confidence interval CI: 1.58–3.42, p=<0.0001), age≥2 years (HR = 2.24; 95% CI: 1.22–4.09, p = 0.01) and preoperative tumour volume (HR = 1.07 per 100 ml; 95% CI: 1.02–1.12, p = 0.01) were significant. The HR for the association of local recurrence and event-free and overall survival with biopsy was not significant (HR = 1.4; 95% CI: 0.9–2.17, p = 0.13; HR = 1.1; 95% CI: 0.85–1.42, p = 0.46 and HR = 1.13; 95% CI: 0.79–1.62, p = 0.51, respectively). These results were not materially different whether FNA or open biopsy were included in the biopsy group or not.
This post hoc analysis provides some reassurance that needle biopsy is not an independent adverse factor for either local recurrence or survival after adjustment for all relevant risk factors. Needle biopsy should not be an automatic criterion to ‘upstage’ WT.
•Biopsy is not associated with local relapse in multivariable analysis.•Results for local relapse are similar for fine needle or cutting needle biopsy.•Automatic ‘upstaging’ is unnecessary in needle biopsied Wilms tumour.•Open biopsy may carry greater risk and should not be used routinely.•Biopsy should be reserved for cases with atypical clinical or radiologic features.
High-risk (HR) metastatic (stage IV) Wilms tumours (WTs) have a particular poor outcome.
Here, we report the results of HR (diffuse anaplastic DA or blastemal type BT) stage IV WT treated patients ...according to the HR arm in the SIOP2001 prospective study.
From January 2002 to August 2014, 3559 patients with WT were included in the SIOP2001 trial. Among the 525 patients (15%) with metastatic WT, 74 (14%) had stage IV HR-WT. The median age at diagnosis was 5.5 years (range: 1.4–18.3). Thirty-four patients (47%) had BT-WT and 40 (53%) had DA-WT. Five-year event-free survival rates were 44 ± 17% and 28 ± 15% for BT-WT and DA-WT, respectively (p = 0.09). Five-year overall survival rates were 53 ± 17% and 29 ± 16% for BT-WT and DA-WT, respectively (p = 0.03). Metastatic complete response after preoperative treatment was significantly associated with outcome in univariate and multivariate analyses (hazards ratio = 0.3; p = 0.01). Postoperative radiotherapy of metastatic sites might also be beneficial. Forty-three of 74 patients experienced a relapse or progression predominantly in the lungs (80%). The median time to relapse/progression after diagnosis was 7.3 months (range: 1.6–33.3) and 4.9 months (range: 0.7–28.4) for BT-WT and DA-WT, respectively (p = 0.67). This is the first prospective evidence of inferior survival of stage IV BT-WT as compared with historical intermediate-risk WT. Survival of patients with stage IV DA-WT has not improved compared to the previous SIOP93-01 study.
These results call for new treatment approaches for patients with HR stage IV WT.
•Fourteen percent of patients with metastatic Wilms tumours (WT) have high-risk (HR) histology.•Patients with metastatic WT with HR histology have a poor survival, despite intensive treatment.•Metastatic complete response after preoperative treatment is associated with outcome.
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