Bevacizumab in pediatric patients: how safe is it?

BACKGROUND: Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF). The safety profile of bevacizumab was evaluated in a cohort of children with either recurrent or poor-prognosis malignancies. PATIENTS AND METHODS: Bevacizumab was administered intravenously at the dosage of 5-10 mg/kg every 14-28 days alone or in combination with other agents. Toxicity was reported according to common toxicity criteria version 4. RESULTS: Seventeen patients received a total of 156 bevacizumab doses (median 5 doses/pt) for a median treatment duration of 2 months (range 1-21). Grade II-III lymphopenia was recorded in 10 patients, while grade III proteinuria and grade I epistaxis occurred in one patient each. Grade III wound dehiscence was observed in one case and 3 severe adverse events (SAEs) were recorded: one reversible posterior leukoencephalopathy syndrome (RPLS) with grade IV seizures and grade IV hypertension, one grade IV hypertension and a post-operative grade IV entero-cutaneous fistula. CONCLUSION: In the present cohort, the overall incidence of SAEs (17%) was higher than previously reported, thus, further studies should be justified to better characterize the safety profile of bevacizumab in the pediatric population.

Foreign children with cancer in Italy.

BACKGROUND: There has been a noticeable annual increase in the number of children coming to Italy for medical treatment, just like it has happened in the rest of the European Union. In Italy, the assistance to children suffering from cancer is assured by the current network of 54 centres members of the Italian Association of Paediatric Haematology and Oncology (AIEOP), which has kept records of all demographic and clinical data in the database of Mod.1.01 Registry since 1989. METHODS: We used the information stored in the already mentioned database to assess the impact of immigration of foreign children with cancer on centres' activity, with the scope of drawing a map of the assistance to these cases. RESULTS: Out of 14,738 cases recorded by all centres in the period from 1999 to 2008, 92.2% were born and resident in Italy, 4.1% (608) were born abroad and living abroad and 3.7% (538) were born abroad and living in Italy. Foreign children cases have increased over the years from 2.5% in 1999 to. 8.1% in 2008.Most immigrant children came from Europe (65.7%), whereas patients who came from America, Asia and Oceania amounted to 13.2%, 10.1%, 0.2%, respectively. The immigrant survival rate was lower compared to that of children who were born in Italy. This is especially true for acute lymphoblastic leukaemia patients entered an AIEOP protocol, who showed a 10-years survival rate of 71.0% vs. 80.7% (p < 0.001) for immigrants and patients born in Italy, respectively. CONCLUSIONS: Children and adolescents are an increasingly important part of the immigration phenomenon, which occurs in many parts of the world. In Italy the vast majority of children affected by malignancies are treated in AIEOP centres. Since immigrant children are predominantly treated in northern Italy, these centres have developed a special expertise in treating immigrant patients, which is certainly very useful for the entire AIEOP network.

Microscopic neoplastic thrombosis in localised nephroblastoma: does it influence outcome?

INTRODUCTION: Microscopic neoplastic thrombosis (MNT) is reported to occur frequently in Wilms tumour (WT). The aim of this study is to determine whether MNT influences prognosis in localised WT. PATIENTS AND METHODS: Records and slides of 80 consecutive, unselected, localised WT patients were retrospectively reviewed. All patients received chemotherapy before surgery according to SIOP Protocol. The median follow-up was 9 years (range 0.5-25.8). The Kaplan-Meier method and the Cox proportional hazard model were applied. RESULTS: MNT was present in 14 (18%) cases. Out of 14 patients with MNT, 6 presented macroscopic thrombosis and 5 had either blastemal predominance or anaplastic histology. The 5-year overall survival (OS) and progression-free survival (PFS) for the whole population were 95% (95% confidence interval, CI, 87-98%) and 91% (95% CI 82-96%), respectively. The 5-year OS and PFS for MNT positive patients were 92% (95% CI 57-99%) and 77% (95% CI 44-92%), while the 5-year OS and PFS for MNT negative patients were 96% (95% CI 87-99%) and 94% (95% CI 85-98%), respectively; the difference was statistically significant (p<0.05) for PFS. In multivariate analysis, only the presence of anaplasia retained significance with a hazard ratio (HR) of 14.8 and 12.9 (p<0.05) for recurrence and death, respectively. CONCLUSION: These data suggest that the presence of MNT increases the risk of recurrence. MNT is associated with well-known prognostic factors, such as macroscopic thrombosis (possibly representing regression of macroscopic involvement) and anaplasia. Further prospective studies are needed to clarify the role of MNT as independent prognostic factor.

Gefitinib in combination with oral topotecan and cyclophosphamide in relapsed neuroblastoma: pharmacological rationale and clinical response.

AIM: Activity and toxiciy of gefitinib in combination with topotecan and cyclophosphamide (CPA) were evaluated in a case-series of relapsed neuroblastoma (NB) patients. The in vitro activity of the combination was also assessed. PROCEDURE: Gefitinib (250 mg/day), topotecan (0.8 mg/m(2)/day), and CPA (50 mg/m(2)/day) (GTC) were administered orally for 14 consecutive days out of 28 days. Antitumor activity of gefitinib as single agent and in combination with either topotecan or CPA was assessed in a panel of NB cell lines. RESULTS: Ninety-two courses were given in 10 patients. Grade 4 neutropenia was observed in 7/92 courses (8%) and grade 4 thrombocytopenia in 8/92 (9%). Two patients had a grade 2 liver toxicity, four a grade 1/2 skin toxicity, and two a grade 1/2 diarrhea. Dose reduction of topotecan and/or CPA was required in eight patients. After four courses, three patients were in partial response (PR) and four with a stable disease (SD), while three experienced a progressive disease (PD). Time to progression (TTP) was 9 months (range, 1-27). After a median follow-up of 16 months (range 5-54), seven patients are died of disease (DOD) and three alive with disease (AWD). All but one patient discontinued oral chemotherapy because of a PD, whilst one patient stopped chemotherapy after 27 months with a SD. In vitro, gefitinib was synergistic with topotecan and additive with CPA. CONCLUSION: The GTC combination was well tolerated and the TTP was encouraging. These promising results, also supported by in vitro evidence, should be further confirmed in a phase II study.

Prolonged response to oral gefitinib, cyclophosphamide, and topotecan in heavily pretreated relapsed stage 4 neuroblastoma: a case report.

A girl with metastatic neuroblastoma diagnosed at 4 years of age experienced an early disseminated relapse after high-dose chemotherapy. After reinduction, compassionate treatment with gefitinib (250 mg/d fixed dose) with oral topotecan (0.8 mg/m(2)/d) and cyclophosphamide (50 mg/m(2)/d) for 14 consecutive days, each course repeated every 28 days, was administered. Complete marrow clearance and metaiodobenzylguanidine response were achieved after 4 courses. After the first course, topotecan and cyclophosphamide were reduced by 25% for grade 4 hematologic toxicity. Subsequent courses were well tolerated. The girl remained progression free for 27 months. This combination may represent a viable therapeutic option and deserves further evaluation in resistant neuroblastoma.