Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)☆.

BACKGROUND: We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274). PATIENTS AND METHODS: The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D. RESULTS: In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m2, three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan-Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3. CONCLUSIONS: The lenvatinib RP2D was 14 mg/m2. Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial (NCT04154189), in pediatric solid tumors in combination with everolimus (NCT03245151), and as a single agent in a basket study with enrollment ongoing (NCT04447755).

Actividad del grupo europeo y avances biológicos en el tratamiento / Activity of European group and biological advances in the treatment

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Synovial sarcoma in children. A single centre experience.

Synovial sarcoma (SS) is a rare disease in the paediatric population, predominating in adolescents. Surgery remains the best treatment strategy for resectable cases. Adjuvant chemotherapy or radiotherapy can be used but have not proven efficacy. Metastatic disease and unsuccessful surgery are major prognostic factors. We describe four cases in children aged 7-13 years old. All of them were affected by SS of upper and lower limbs, and had satisfactory resections with different outcomes in spite of receiving diverse chemotherapy regimens. One of them is at the moment under treatment for relapse, two are disease-free and another died after metastatic disease.

Synovial sarcoma in children. A single centre experience

Synovial sarcoma (SS) is a rare disease in the paediatric population, predominating in adolescents. Surgery remains the best treatment strategy for resectable cases. Adjuvant chemotherapy or radiotherapy can be used but have not proven efficacy. Metastatic disease and unsuccessful surgery are major prognostic factors. We describe four cases in children aged 7-13 years old. All of them were affected by SS of upper and lower limbs, and had satisfactory resections with different outcomes in spite of receiving diverse chemotherapy regimens. One of them is at the moment under treatment for relapse, two are disease-free and another died after metastatic disease (AU)

[Renal tumors in infants aged less than 1 year]. / Tumores renales en niños menores de un año.

OBJECTIVE: To determine the frequency and distribution of primary renal tumors diagnosed in a pediatric oncology unit in children younger than 1 year and identify their clinical and histopathological characteristics, the treatment used, and outcomes. MATERIAL AND METHODS: We retrospectively reviewed the medical records of infants with primary tumors of the kidney diagnosed between January 1972 and February 2003. RESULTS: A total of 137 tumors were diagnosed in our unit during the period studied. Of these, 25 (18.2 %) occurred in infants aged less than 1 year. There were 17 boys and 8 girls. The most prevalent tumor in this age group was Wilms' tumor (WT) in 15 patients, followed by mesoblastic nephroma (MN) in 9 patients and rhabdoid tumor in 1 patient. The mean age at diagnosis of WT was 4.8 months (range: 1 day-11 months), with a median of 5.03 months. The median age at diagnosis of MN was 1 day (range: 1 day-3 months). Presenting symptoms consisted of abdominal mass in 20 patients, hematuria in 4 patients and intestinal pseudo-occlusion (MN) in 1 patient. High blood pressure was found in 12 of the 25 patients. Among the 15 WT, 9 were stage I, 1 was stage II, one was stage III, 2 were stage IV, and 1 was stage V. One patient died before surgery. Overall survival at 5 years was 0.67 (SE 0.12) for WT and 0.89 (SE 0.1) for MN, respectively, with a mean follow-up of 290 months. CONCLUSIONS: MN was more frequent than WT in infants aged less than 6 months. The first-line therapy in these patients is surgery since this type of tumor shows little chemosensitivity and chemotherapy is poorly tolerated in infants.

Tumores renales en niños menores de un año / Renal tumors in infants aged less than 1 year

Objetivo: Conocer la frecuencia y distribución de los tumores renales diagnosticados en una unidad de oncología pediátrica en niños menores de un año, sus características clínicas, anatomopatológicas, tratamientos utilizados y evolución. Material y métodos: Estudio retrospectivo de tumores renales primarios diagnosticados en lactantes en un hospital pediátrico, desde 1972 hasta febrero de 2003. Resultados: Obtuvimos 25 niños menores de un año (18,2 %), de un total de 137 tumores renales registrados. Diecisiete niños y 8 niñas. El más frecuente fue el nefroblastoma (15/25), seguido del nefroma mesoblástico (9/25), y uno fue un tumor rabdoide. La media de edad al diagnóstico fue de 4,8 meses (rango, 1 día-11 meses), la mediana de 5,03 meses; para los nefromas mesoblásticos la mediana fue de 1 día (rango, 1 día-3 meses). La forma de presentación fue como masa abdominal en 20 de ellos, en cuatro hematuria y un recién nacido empezó con obstrucción intestinal (nefroma mesoblástico). Presentaron hipertensión arterial 12/25 niños; 9/15 casos de nefroblastomas eran estadio I; uno, estadio II; uno, estadio III; dos, estadio IV; uno, estadio V, y uno falleció antes de la cirugía. La supervivencia global de los nefroblastomas a los 5 años es de 0,67 (error estándar [EE]: 0,12); y del nefroma mesoblástico de 0,89 (EE: 0,1), con un tiempo de supervivencia media de 290 meses. Conclusiones: En los niños menores de 6 meses el nefroma mesoblástico es más frecuente que el tumor de Wilms, siendo el tratamiento inicial de elección la cirugía, ya que este tipo de tumor es poco quimiosensible y la quimioterapia es peor tolerada en los lactantes

Objective: To determine the frequency and distribution of primary renal tumors diagnosed in a pediatric oncology unit in children younger than 1 year and identify their clinical and histopathological characteristics, the treatment used, and outcomes. Material and methods: We retrospectively reviewed the medical records of infants with primary tumors of the kidney diagnosed between January 1972 and February 2003. Results: A total of 137 tumors were diagnosed in our unit during the period studied. Of these, 25 (18.2 %) occurred in infants aged less than 1 year. There were 17 boys and 8 girls. The most prevalent tumor in this age group was Wilms' tumor (WT) in 15 patients, followed by mesoblastic nephroma (MN) in 9 patients and rhabdoid tumor in 1 patient. The mean age at diagnosis of WT was 4.8 months (range: 1 day-11 months), with a median of 5.03 months. The median age at diagnosis of MN was 1 day (range: 1 day-3 months). Presenting symptoms consisted of abdominal mass in 20 patients, hematuria in 4 patients and intestinal pseudo-occlusion (MN) in 1 patient. High blood pressure was found in 12 of the 25 patients. Among the 15 WT, 9 were stage I, 1 was stage II, one was stage III, 2 were stage IV, and 1 was stage V. One patient died before surgery. Overall survival at 5 years was 0.67 (SE 0.12) for WT and 0.89 (SE 0.1) for MN, respectively, with a mean follow-up of 290 months. Conclusions: MN was more frequent than WT in infants aged less than 6 months. The first-line therapy in these patients is surgery since this type of tumor shows little chemosensitivity and chemotherapy is poorly tolerated in infants

[Attention process training application within an intervention project on attentional processes in children with cancer]. / Aplicacion del Attention Process Training dentro de un proyecto de intervencion en procesos atencionales en niños con cancer.

INTRODUCTION: Childhood cancer treatments have made a spectacular advance in recent years, obtaining survival rates of about 70%. These survival rates have permitted many children to reach adulthood, but also involve the appearance of previously unknown neurocognitive sequelae because of high mortality. DEVELOPMENT: Neuropsychological evaluation allows the detection of these deficits and the design of intervention. In children, rather than a loss of function there is a loss of the capacities that should develop in comparison with his/her peers. To obtain a base line to determine the affected and altered areas, it is equally vital to assess the acute and long term effects so as to evaluate the success of the intervention program. Attention Process Training (APT) is an individualized application program of attentional exercises of varying complexity in sustained, selective, alternating and divided attention. This program combines methods and techniques of cerebral damage rehabilitation, as well as educational and clinical psychology. It is completed with a self instruction training which is applied in situations of daily life. CONCLUSIONS: Child cancer treatment continues to carry long term neurocognitive sequelae. Neuropsychological evaluation is basic for its detection, allowing relevant information to be offered to parents and teachers, so as to facilitate design of individualized rehabilitation procedures. Attention training is basic for this type of population with generalized damage related to white matter, and forms part of a wider rehabilitation process that enhance the ecological validity of the program.

[Evaluation of a home care program for children with cancer]. / Evaluación de un programa de hospitalización a domicilio para niños con cáncer.

The home care team dependent from the pediatric oncology unit in our institution started working in April, 1997. We evaluate in this paper the medical activities accomplished in seventeen month experience. The team is constituted by a pediatric oncologist, two pediatric nurses and a clinical assistant with experience in the specialty. The geographic area we cover is la Communidad Valenciana. We directly attend children living in Valencia city and its metropolitan area. For the rest of patients, we coordinate the interventions of the local primary care teams and local hospitals. 127 patients have been admitted in the home care unit in 433 occasions. The immediate reasons for the admission were: early discharge from the hospital (61%), followed by the administration of antibiotics (18%) and chemotherapy (12%) at home. We attended 17 children in the terminal phase of their diseases. Five of them required opioid treatment for pain control. Six out of eight patients living in the area of direct intervention of the home care team died at home. The most common cause of discharge (73%) was the achievement of the goals planned when the patient was included in the program. Only in two cases (0.5%) we did not found enough cooperation from the parents and the treatment was completed in the hospital. This program has been well accepted by our patients and their parents and permits to shorten the stay in the hospital.

Evaluación de un programa de hospitalización a domicilio para niños con cáncer / Evaluation of a home care program for children with cancer

La hospitalización a domicilio para niños con cáncer empezó a funcionar en la Unidad de Oncología Pediátrica (UOP) del Hospital Infantil La Fe en abril de 1997. Recogemos en este trabajo la asistencia realizada en los primeros 17 meses de experiencia. El equipo responsable, integrado en la UOP, está constituido por un oncólogo pediatra, dos enfermeras y una auxiliar con amplia experiencia en la especialidad. El área de cobertura geográfica abarca la totalidad de la Comunidad Valenciana. Atendemos de forma directa a los pacientes residentes en el área metropolitana de la ciudad de Valencia; en el resto, la asistencia es delegada, en coordinación con los equipos de atención primaria y hospitales comarcales. Un total de 127 pacientes han sido ingresados en hospitalización a domicilio en 433 ocasiones. El motivo de ingreso más frecuente fue el alta hospitalaria precoz (61 por ciento), seguido por la administración intravenosa de antibióticos (18 por ciento) o quimioterapia (12 por ciento) en el domicilio. Diecisiete pacientes fueron atendidos en sus casas durante la fase terminal de la enfermedad, para tratamiento paliativo. Cinco de ellos precisaron tratamiento con opioides para controlar adecuadamente el dolor. Seis de los 8 pacientes residentes en el área metropolitana de Valencia fallecieron en sus domicilios. La causa más frecuente de alta del programa fue el logro de las metas programadas al ingreso (73 por ciento). Sólo en 2 casos (0,5 por ciento) no hubo cooperación por parte de los padres y el tratamiento se completó en el hospital. Este programa es bien aceptado por nuestros pacientes y sus familias y permite acortar la estancia en el hospital (AU)

[Central nervous system tumors in children less than three years of age]. / Tumores de sistema nervioso central en niños menores de 3 años.

OBJECTIVE: Central nervous system (CNS) tumors are the most frequent solid tumors in children. Twelve to twenty percent are diagnosed in patients younger than two years of age and these patient present more morbidity and mortality due to the illness and the treatment itself. PATIENTS AND METHODS: A retrospective study of CNS tumors in children younger than three years of age diagnosed in our hospital between 1985 and 1995 was carried out. RESULTS: We treated 21 patients between 1985 and 1995. There were 10 male and 11 females. The mean age was 20.3 months (range: 0-32 months). The mean time between symptoms and treatment was 2.4 months (range: 0-18 months). The most common symptoms included ataxia, nausea and vomits. The most common locations of the tumor were: infratentorial (57.1%) and supratentorial (38.1%). Complete surgery was performed in 3 patients, subtotal in 10, partial in 5, and a biopsy in 2. The anatomical-pathological diagnosis was: astrocytoma (6), ependinoma (5), meduloblastoma (4), ganglioglioma (1), neuroblastoma (1), and primitive neuroectodermic tumor (1). We could not document the histology in 3 patients. Ten patients received chemotherapy that was well tolerated and 14 received radiotherapy whose sequels were updated. The mean follow-up period was 44.42 months (range: 0-136 months). Overall survival was 42.86%. There were no statistically significant differences in survival between those who were irradiated and those who were not, nor between those with supra-or infratentorial tumors. CONCLUSIONS: CNS tumors in children younger than three years of age have a worse prognosis than in older children. New therapeutic schedule with chemotherapy are being tested to avoid radiotherapy side-effects.

[Down's syndrome and leukemia]. / Síndrome de Down y leucemia.

OBJECTIVE: Children with Down's Syndrome (DS) have a high risk for leukemia and need special clinical management. For this reason we have reviewed our experience. PATIENTS AND METHODS: All children with DS diagnosed a having acute leukemia during a 21-year period were reviewed retrospectively. Treatment was administered according to current protocols in our unit at the time of diagnosis without any initial modification. RESULTS: There were 13 children with DS and acute leukemia [6 ALL, 4 AML and 3 transient leukemias (TL)]. No patient presented CNS leukemia at diagnosis. All children with AML and DS were under three years of age and standard treatments did not achieve satisfactory results. TL regressed in two newborns without developing AMKL later. Five out of six patients with DS and ALL achieved complete remission. Currently, 4 of these children are alive and off therapy. Toxicities related to treatment were observed in almost all of the patients. CONCLUSIONS: Children with DS suffer a higher risk of developing leukemia. They should receive standard protocols, but aggressive supportive care might be provided as they have a higher incidence of treatment related toxicities. Prognosis of these children is similar or even better in some cases than children without DS. TL is a true neoplastic process capable of spontaneous remission and it can progress to AMKL.

[Surgical treatment of pediatric pulmonary metastases]. / Tratamiento quirúrgico de las metástasis pulmonares pediátricas.

OBJECTIVE: We comment and update the surgical treatment for pulmonary metastases (PM) within a multidisciplinary approach for paediatric cancer. MATERIAL AND METHODS: We analyse patients with PM who have been operated between 1976-1996. Scientific literature published in the last 25 years (Cancerlit and Medline) was reviewed. RESULTS: PM from 13 patients were removed. Seven were males and 6 females with a mean age 5 4/12 years (range: 11 months- 12 3/12 years). Diagnoses were Wilms' tumour (7), osteosarcoma (3), Ewing sarcoma (1), rabdomiosarcoma (1), Yolk sac tumour (1). PM were unilateral in 7 cases and bilateral in six cases. PM appeared synchronically in four patients and metacronically in nine cases (3 of these after chemotherapy). All patients received chemotherapy and four of them local radiotherapy. Surgery consisted on radical segmentectomy and only one patient needed lobectomy due to a local relapse. Nowadays five patients (38%) are in complete remission with a mean follow-up from surgery of 11 11/12 years (range: 6 3/12-20 years). CONCLUSIONS: Metastasectomy is an important surgical technique in global treatment of children with PM and for a selected group of patients it can offer the only opportunity for curation.

[Granulocyte recovery and early infection complications in oncologic pediatric patients treated with hematopoietic stem cell transplantation]. / Prendimiento de la serie blanca y complicaciones infecciosas precoces en pacientes oncológicos pediátricos sometidos a transplante de precursores hematopoyéticos.

OBJECTIVE: Infections during the early post-BMT period are a major cause of morbidity in BMT recipients. We report our experience in a single institution. PATIENTS AND METHODS: Clinical reports from all BMT patients between 1989-1995 were reviewed retrospectively. Routine reverse isolation techniques, prophylactic measures and central venous catheter were used in all cases and starting in 1992, G-CSF was also used. Fever in the aplasia period was considered a sign of infection. RESULTS: Sixty-three BMTs were performed between 1989 and 1995 with 30 being ABMT, 17 allogenic and 16 PBSC. The time for granulocyte recovery was shorter in PBSC + G-CSF patients (d + 11). There were 65 infections in the early post-BMT period: 22 were microbiologically confirmed, 18 of them being of bacterial origin and 14 disseminated. Gram positive bacteria were predominant. There were 6 cases of interstitial pneumonitis, with 3 of them being lethal. Infection-related mortality was 6.3%. CONCLUSIONS: 1) BMTs can be safely performed using conventional reverse isolation. 2) The use of PBSC and G-CSF accelerates granulocyte recovery in BMTs. 3) Infections due to Gram positive bacteria were a major cause of morbidity in our series. 4) Pneumonitis and fungal infections are the most frequent lethal infections in our patients.

[Non-Hodgkin's lymphoma in childhood: 19-year experience in a pediatric oncology unit]. / Linfomas no Hodgkin en la infancia: 19 años de experiencia en una unidad de oncología pediátrica.

Ninety-one patients with Non-Hodgkin's Lymphoma (NHL) were treated in our Pediatric Oncology Unit during a 19 year period. The median age at diagnosis was 5.8 years and there was a higher incidence in males. All patients were classified according to Murphy's stages and Rappaport's modified classification. Advanced disease and non-lymphoblastic histology were prevailing. Chemotherapy was the preferred treatment. Forty-seven patients (54%) are alive with a median follow-up period of 6.2 years. Actuarial survival rate at 5 years is 0.6. Advances in chemotherapy led to an increase in NHL patient's survival. Twenty patients died because of the disease and 21 because of fatal complications.

[Retinoblastoma: multidisciplinary treatment in a group of 32 patients]. / Retinoblastoma: tratamiento multidisciplinario en una serie de 32 pacientes.

Thirty-two children with retinoblastoma (RTB) were treated in our oncology unit between September 1981 and October 1989. There were 18 unilateral RTB and 14 bilateral. The median age at diagnosis was 24 months. Leukocoria was the most common sign of presentation (66%). All patients were treated with a protocol based on Reese-Ellsworth classification and the anatomo-clinic extension. Thirty patients were enucleated (7 bilaterally), 14 of which needed coadjuvant chemotherapy and 6 orbital radiotherapy. Two patients died, one from each group. The disease-free survival rate is 90.6% with a medium follow-up of 43.5 months. Seven children went blind because of bilateral enucleation and seven present facial deformity caused by radiotherapy. We underline the importance of improving the effectiveness of conservative treatment in order to reduce the number of enucleation.