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Purpose: Low- and middle-income countries (LMICs) experience the burden of 80% of new childhood cancer cases worldwide, with cure rates as low as 10% in some countries. Metronomics combines frequent administrations of low-dose chemotherapy with drug repurposing, which consists of using already-approved drugs for new medical applications. With wide availability, limited costs, and little infrastructure needs, metronomics can be part of constraint-adapted regimens in these resource-limited settings-with the understanding that metronomics shall not be a substitute for standard treatments when available and doable. Our study aims to describe the experience, practices, opinions, and needs in metronomics of physicians working in LMICs., Methods: An online questionnaire was sent to more than 1,200 physicians in pediatric oncology networks in LMICs. Items included the type of center, physician's demographics, experience in pediatric oncology, and experience with current knowledge of metronomics. Opinions and perspectives were explored using multiple-answer and open questions., Results: Of physicians, 17% responded. Of respondents, 54.9% declared that they had already used a metronomic regimen. The most frequently cited repositioned drugs were celecoxib (44%) followed by propranolol and valproic acid (17%). Respondents highlighted the advantages of outpatient use (20%) and expected low toxicity (24%). In considering the drawbacks of metronomics, 47% of responses highlighted the lack of scientific evidence or guidelines, 33% the availability or affordability of drugs, and 18% the problem of acceptance or compliance. Of physicians, 79% believed that use of metronomics will spread in LMICs in the near future and 98% of them were willing to participate in international metronomic protocols or registries., Conclusion: Metronomics is already used in LMICs and is a potential answer to unmet needs in pediatric oncology. There is room for improvement in the availability of drugs and a necessity to develop collaborative protocols and research to generate level A evidence.

The purpose of the study was to evaluate the outcome of patients under 18 months diagnosed with neuroblastoma. Between April 2006 and December 2013, 45 consecutive patients followed in Hospital de Pediatría Garrahan, were retrospectively reviewed. With a median age of 9.3 months (1-18 months) N-myc amplification was detected in 5 out of 38 patients, 1p deletion (del1p) in 4 patients, and 11q aberration in one patient. With a median follow-up of 53 (range: 6-109 months), at 24 months the event free survival (EFS) of all patients was 83% (SE 6%) and overall survival (OS) of 88% (SE 5%). Significant difference was found in OS and EFS between patients with stages L1, L2 and Ms vs. stage M (p = 0.01 and p = 0.01 respectively). EFS for each stage: L1 85% (SE 7%), L2 100%, MS 100%, vs. M 55% (SE 16%). OS: L1 90% (SE 6%), L2 100%, MS 100%, vs. M 66% (SE 15%). OS and EFS results are similar to those reported in international studies. However, better identification of biological prognostic factors will warr ant accurate staging and consequently an appropriate treatment.

High-dose chemotherapy (HDC) followed by autologous stem cell rescue (ASCR) is the only curative treatment for metastatic retinoblastoma, but its feasibility in developing countries is unknown. We report 11 consecutive children (six unilateral) treated in three South-American middle-income countries with HDC-ASCR. One patient had metastatic retinoblastoma at diagnosis and the remaining ones had a metastatic relapse. Metastatic sites included BM=6, bone=4, orbit=5 and central nervous system (CNS)=4. All patients received induction with conventional chemotherapy achieving CR at a median of 5.7 months from the diagnosis of metastasis. Conditioning regimens included carboplatin and etoposide with thiotepa in six or with CY in four or melphalan in one patient. All patients engrafted after G-CSF-mobilized peripheral blood ASCR and no toxic deaths occurred. Two children received post-ASCR CNS radiotherapy. Seven children have disease-free survival (median follow-up 39 months). CNS relapse, isolated (n=3) or with systemic relapse (n=1), occurring at a median of 7 months after ASCT was the most common event. In the same period, five children with metastatic retinoblastoma did not qualify for HDC-ASCR and died. We conclude that HDC-ASCR is a feasible and effective treatment for children with metastatic retinoblastoma in middle-income countries.

Topotecan is a promising drug with activity against retinoblastoma, however, attaining therapeutic concentrations in the vitreous humor is still a challenge for the treatment of vitreous seeds in retinoblastoma. Our aim was to characterize topotecan pharmacokinetics in vitreous and aqueous humor, and to assess the systemic exposure after intra-vitreal injection in rabbits as an alternative route for maximizing local drug exposure. Anesthetized rabbits were administered intra-vitreal injections of 5 microg of topotecan. Vitreous, aqueous, and blood samples were collected at pre-defined time points. A validated high-performance liquid chromatography assay was used to quantitate topotecan (lactone and carboxylate) concentrations. Topotecan pharmacokinetic parameters were determined in vitreous, aqueous and plasma using a compartmental analysis. Topotecan lactone concentrations in the vitreous of the injected eye were about 8 ng/mL 48 h after drug administration. The median maximum vitreous, aqueous and plasma total topotecan concentrations (C(max)) were 5.3, 0.68 and 0.21 microg/mL, respectively. The C(max) vitreous/aqueous of treated eyes and the C(max) vitreous/plasma were approximately 8 and 254, respectively. Total topotecan exposure (AUC) in the vitreous of the injected eye was 50 times greater than the total systemic exposure. These findings suggest that intra-vitreal administration of only 5 microg of topotecan reaches significant local levels over an extended period of time while minimizing systemic exposure in the rabbit. Intra-vitreal topotecan administration offers a promising alternative route for enhanced drug exposure in the vitreous humor with potential application for treatment of vitreal seeds in retinoblastoma while avoiding systemic toxicities., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Previous studies of the penetration of carboplatin into the vitreous have depended on unaffected animals or on animal models for other cancers. The objective of this study was to determine the intraocular levels of carboplatin following intravenous administration of carboplatin in the treatment of human intraocular retinoblastoma. Eight patients with bilateral intraocular retinoblastoma were treated in a consistent fashion with intravenous carboplatin. One additional patient was similarly treated, but enucleated one month later. Samples were taken from those nine eyes after enucleation one to two hours after the administration of 18.7 mg/kg (560 mg/m( 2) for patients more than 12 kg) of intravenous carboplatin, and carboplatin concentrations in the aqueous and vitreous were then measured by atomic absorption spectrometry. The mean concentration measured in the aqueous was 5.13 microg/ml and in the vitreous 4.05 microg/ml, and vitreal concentrations were an average of 80% of aqueous concentrations. In one patient, a vitreous concentration of carboplatin was detected after an interval of one month that was 10% of the levels found in the samples enucleated one hour post-administration. These concentrations are much higher than previous animal studies would predict, and are similar to levels measured in unaffected animals when the drug is given after the use of cryotherapy. The concentration also approaches levels previously shown to be toxic to the retina. This elevation in carboplatin concentration may be due to disruption of the blood-vitreous barrier by active tumor.

Background: Acute myeloid leukemia (AML) is well-recognized as one of the most important second malignancies. We report the occurrence of secondary AML (sAML) in our institution., Procedure: From September 1987 to August 1996 we have observed sAML in 9 patients (median age 4 years), 5 of them previously treated for hematologic malignancies (group I): acute lymphoblastic leukemia (n = 2), AML (n = 1), non-Hodgkin lymphoma (n = 1). Hodgkin disease (n = 1), and 4 of these 9 patients treated for solid tumors (group II): neuroblastoma (n = 1), retinoblastoma (n = 1), Wilms tumor (n = 1), and central nervous system germinoma (n = 1)., Results: All the patients had topoisomerase II inhibitors as part of treatment of their first malignancy, but only 5 patients received epipodophyllotoxins. Alkylating agents were part of primary therapy in 8 of 9 patients. The latency period for the development sAML was 26.5 (range = 2-55) months. The morphologic FAB features of sAML were M5 (n = 5), M4 (n = 3), and M2 (n = 1). Cytogenetic studies showed r11q23 in 3 patients, all of them with prior hematological malignancies. Initial therapy for sAML in all cases was chemotherapy (including cytarabine in combination with idarubicin and etoposide or doxorubicin or mitoxantrone). Three patients died during induction and 6 achieved complete hematologic response. Three of these patients remain disease free at +15, +51, and +99 months post-remission (including one post allogeneic BMT). The remaining 3 patients died, 1 in complete remission one month after diagnosis and 2 relapsed and died with progressive disease (one post allogeneic BMT)., Conclusions: Secondary AML is a sequela of oncologic treatments with specific cytogenetic abnormalities and poor outcome. A few patients can achieve long-term survival even with standard chemotherapy.