International Society of Paediatric Oncology (SIOP) Global Mapping Program: Analysis of healthcare centers in countries of the Latin American Society of Pediatric Oncology (SLAOP).

BACKGROUND: The International Society of Paediatric Oncology Society Global Mapping Program aims to describe the local pediatric oncology capacities. Here, we report the data from Latin America. METHODS: A 10-question survey was distributed among chairs of pediatric oncology services. Centers were classified according to patient volume into high- (HVC; 100 or more new cases per year), medium- (MVC; 31-99 cases), and low-volume centers (LVC; 30 cases or less), respectively. National referral centers (NRC) were identified. RESULTS: Total 307 centers in 20 countries were identified (271 responded), and 264 responses were evaluable, accounting for 78% of the expected cases (21,359 cases per year). Seventy-seven percent of patients are treated in public centers, including additional support by civil society organizations. We found that 66% of the patients are treated in 70 centers of excellence, including 21 NRC. There was a median of one pediatric oncologist every 21 newly diagnosed patients (44 for NRC), and in 84% of the centers, nurses rotated to other services. A palliative care team was lacking in 25% of the centers. LVC with public funding have significantly lower probability of having a palliative care team or trained pediatric oncology surgeons. Psychosocial, pharmacy, and nutrition services were available in more than 93% of the centers. No radiotherapy facility was available on campus in nine of 21 NRC. CONCLUSIONS: Most children with cancer in Latin America are treated in public HVC. There is a scarcity of pediatric oncologists, specialized nurses and surgeons, and palliative care teams, especially in centers with public funding.

International Society of Paediatric Oncology (SIOP) Global Mapping Programme: Latin American Society of Pediatric Oncology (SLAOP) country-level report.

BACKGROUND: Latin American countries are improving childhood cancer care, showing strong commitment to implement the Global Initiative for Childhood Cancer, but there are scant publications of the situation at a continental level. METHODS: As part of the International Society of Paediatric Oncology Global Mapping project, delegates of each country participating in the Latin American Society of Pediatric Oncology (SLAOP) and chairs of national pediatric oncology societies and cooperative groups were invited to provide information regarding availability of national pediatric cancer control programs (NPCCP), pediatric oncology laws, pediatric oncology tumor registries, and training programs and support to diagnosis and treatment. RESULTS: Nineteen of the 20 countries participating in SLAOP responded. National delegates reported nine countries with NPCCP and four of them were launched in the past 5 years. National pediatric tumor registries are available in eight countries, and three provided published survival results. Fellowship programs for training pediatric oncologists are available in 12 countries. National delegates reported that eight countries provide support to most essential diagnosis and treatments and 11 provide partial or minimal support that is supplemented by civil society organizations. Seven countries have a pediatric oncology law. There are three international cooperative groups and four national societies for pediatric oncology. CONCLUSION: Despite many challenges, there were dramatic advances in survivorship, access to treatment, and availability of NPCCP in Latin America. Countries with highest social development scores in general provide more complete support and are more likely to have NPCCP, training programs, and reported survival results.

Prognostic value of xenograft engraftment in patients with metastatic high-risk neuroblastoma.

BACKGROUND: Successful engraftment of human cancer biopsies in immunodeficient mice correlates with the poor prognosis of patients. This was reported 30 years ago for children with neuroblastoma, but the standard of care treatment evolved significantly during the last 15 years, leading to improved survival of these patients. Here, we evaluated the association of patient-derived xenograft (PDX) engraftment and prognosis in patients receiving up-to-date treatments for cancers classified as metastatic (stage M) high-risk neuroblastoma (HR-NB) by the International Neuroblastoma Risk Group Staging System (INRGSS). METHODS: We obtained biopsies from patients with stage M HR-NB. We inoculated biopsy fragments subcutaneously in mice. We studied the association of PDX engraftment with event-free survival (EFS) and overall survival (OS) of patients. RESULTS: Since 2009, we established 17 PDX from 97 samples of 66 patients with stage M HR-NB, with a follow-up of at least two years. Factors associated with higher probability of engraftment were the death as outcome (p = .0006) and the amplification of the gene MYCN in tumors (p = .0271). Patients whose biopsies established a PDX had significantly shorter EFS and OS (p = .0039 and .0002, respectively) than patients whose samples did not engraft. The association of PDX engraftment and OS was significant in patients without MYCN amplification (p = .0041), but not in patients with MYCN amplification (p = .2707). CONCLUSION: Positive PDX engraftment is a factor related to poor prognosis and fatal outcome in patients with stage M HR-NB treated with up-to-date therapies.

Outcomes of SARS-CoV-2 infection in 126 children and adolescents with central nervous system tumors.

BACKGROUND: The Global Registry of COVID-19 in Childhood Cancer (GRCCC) seeks to describe the natural history of SARS-CoV-2 in children with cancer across the world. Here, we report the disease course and management of coronavirus disease 2019 (COVID-19) infection in the subset of children and adolescents with central nervous system (CNS) tumors who were included in the GRCCC until February 2021, the first data freeze. PROCEDURE: The GRCCC is a deidentified web-based registry of patients less than 19 years of age with cancer or recipients of a hematopoietic stem cell transplant and laboratory-confirmed SARS-CoV-2 infection. Demographic data, cancer diagnosis, cancer-directed therapy, and clinical characteristics of SARS-CoV-2 infection were collected. Outcomes were collected at 30 and 60 days post infection. RESULTS: The GRCCC included 1500 cases from 45 countries, including 126 children with CNS tumors (8.4%). Sixty percent of the cases were from middle-income countries, while no cases were reported from low-income countries. Low-grade gliomas, high-grade gliomas, and CNS embryonal tumors were the most common CNS cancer diagnoses (67%, 84/126). Follow-up at 30 days was available for 107 (85%) patients. Based on the composite measure of severity, 53.3% (57/107) of reported SARS-CoV-2 infections were asymptomatic, 39.3% (42/107) were mild/moderate, and 6.5% (7/107) were severe or critical. One patient died from SARS-CoV-2 infection. There was a significant association between infection severity and absolute neutrophil count less than 500 (p = .04). Of 107 patients with follow-up available, 40 patients (37.4%) were not receiving cancer-directed therapy. Thirty-four patients (50.7%) had a modification to their treatment due to withholding of chemotherapy or delays in radiotherapy or surgery. CONCLUSION: In this cohort of patients with CNS tumors and COVID-19, the frequency of severe infection appears to be low, although severe disease and death do occur. We found that greater severity was seen in patients with severe neutropenia, although treatment modifications were not associated with infection severity or cytopenias. Additional analyses are needed to further describe this unique group of patients.

How we approach conservative treatment of retinoblastoma in South America in the era of local ocular treatments: A consensus of the Grupo America Latina de Oncologia Pediatrica (GALOP).

Local therapies are increasingly used for ocular preservation in retinoblastoma. In middle-income countries, these techniques pose specific challenges mostly related to more advanced disease at diagnosis. The Grupo de America Latina de Oncología Pediátrica (GALOP) developed a consensus document for the management of conservative therapy for retinoblastoma. Intra-arterial chemotherapy (OAC) is the preferred therapy, except for those with less advanced disease or age younger than 6 months. OAC allowed for a reduction in the use of external beam radiotherapy in our setting. Intravitreal chemotherapy is the preferred treatment for vitreous seeding. Enucleation is the treatment of choice for eyes with advanced disease.

Identification of immunosuppressive factors in retinoblastoma cell secretomes and aqueous humor from patients.

The microenvironment of retinoblastoma, the solid malignancy of the developing retina, is immunosuppressive. To study the interactions between tumor-associated microglia/macrophages (TAMs) and tumor cells in retinoblastomas, we analyzed immunohistochemistry markers in 23 patient samples and characterized 105 secreted cytokines of 11 retinoblastoma cell models in culture. We detected profuse infiltration of CD163+ protumoral M2-like polarized TAMs in eyes enucleated due to cancer progression. Previous treatment of patients increased the number of TAMs but did not affect M2-like polarization. M2-like microglia/macrophages were almost absent in five eyes obtained from children enucleated due to nontumoral causes. CD8+ tumor-infiltrating lymphocytes (TILs) were moderately abundant in tumor eyes and very scarce in nontumoral ones. The expression of the immune checkpoint molecule PD-L1 was absent in 95% of the tumor samples, which is concordant with the finding of FOXP3+ Tregs infiltrating tumors. We confirmed the pathology results using single-cell transcriptome analysis of one tumor. We identified the cytokines extracellular matrix metalloproteinase inducer (EMMPRIN) and macrophage migration inhibitory factor (MIF), both with reported immunosuppressive activity, secreted at high levels in retinoblastoma primary cell cultures. Gene expression analysis of a large retinoblastoma cohort and single-cell transcriptome analysis confirmed that MIF and EMMPRIN were significantly upregulated in retinoblastomas, which led us to quantify both proteins by immunoassays in liquid biopsies (aqueous humor obtained from more than 20 retinoblastoma patients). We found a significant increase in the concentration of MIF and EMMPRIN in cancer patients, compared to 12 noncancer ones. Finally, we showed that macrophages derived from peripheral blood mononuclear cells increased the expression of markers of M2-like polarization upon exposure to retinoblastoma-conditioned medium or recombinant MIF. Overall, our findings suggest that retinoblastoma cell secretions induce the protumoral phenotype of this tumor. Our results might have clinical impact in the fields of biomarkers and treatment. © 2022 The Pathological Society of Great Britain and Ireland.

Impact of the COVID-19 pandemic on pediatric oncology providers globally: A mixed-methods study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) disrupted pediatric oncology care globally, increasing demands on health care providers (HCPs) who adapted to continue care. This study sought to characterize the pandemic's impact on pediatric oncology HCPs worldwide. METHODS: A 60-item survey focused on changes to clinical care, resources, and effects on clinicians. A diverse subgroup of institutions was purposefully selected for focus groups that explored teamwork, communication, and changes to care delivery. RESULTS: The survey included 311 responses from 213 institutions representing 79 countries. Sixteen institutions participated in 19 multidisciplinary focus groups in 8 languages. Decreased clinical staff availability was cited by 51% of institutions as a major impact. Staffing modifications included decreased provider availability (66% of institutions), roles or responsibility changes, and transfer outside the specialty. Physical effects included frequent COVID-19 illness; 8% of respondents reported HCP deaths. Fifty percent of providers did not have the necessary personal protective equipment. HCPs also experienced psychological distress and financial concerns. Findings indicated more frequent impact on nurses than other providers. Impacts were described across all hospital resource levels, with staffing modifications more frequent in countries with higher COVID-19 incidence (P < .001) and mortality rate (P = .004). Focus groups revealed negative impacts were stabilized by increased teamwork, communication, contributions outside usual roles, policies aimed at optimizing safety, and feeling that they were contributing. CONCLUSIONS: COVID-19 had a profound impact on the pediatric oncology workforce, creating challenging modifications to staffing and resulting in physical, psychological, and financial distress. Despite these challenges, HCPs caring for children with cancer came together to continue to provide high-quality care.

Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study.

BACKGROUND: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. METHODS: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection. FINDINGS: Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8-8·8]; p<0·0001) and upper-middle-income (1·6 [1·2-2·2]; p=0·0024) country status; age 15-18 years (1·6 [1·1-2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mm3 (2·5 [1·8-3·4]; p<0·0001), absolute neutrophil count of 500 or less cells per mm3 (1·8 [1·3-2·4]; p=0·0001), and intensive treatment (1·8 [1·3-2·3]; p=0·0005). Factors associated with treatment modification included upper-middle-income country status (OR 0·5 [95% CI 0·3-0·7]; p=0·0004), primary diagnosis of other haematological malignancies (0·5 [0·3-0·8]; p=0·0088), the presence of one of more COVID-19 symptoms at the time of presentation (1·8 [1·3-2·4]; p=0·0002), and the presence of one or more comorbidities (1·6 [1·1-2·3]; p=0·020). INTERPRETATION: In this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illness. FUNDING: American Lebanese Syrian Associated Charities and the National Cancer Institute.

Response criteria for intraocular retinoblastoma: RB-RECIST.

Standardized guidelines for assessing tumor response to therapy are essential for designing and conducting clinical trials. The Response Evaluation Criteria In Solid Tumors (RECIST) provide radiological standards for assessment of solid tumors. However, no such guidelines exist for the evaluation of intraocular cancer, and ocular oncology clinical trials have largely relied on indirect measures of therapeutic response-such as progression-free survival-to evaluate the efficacy of treatment agents. Herein, we propose specific criteria for evaluating treatment response of retinoblastoma, the most common pediatric intraocular cancer, and emphasize a multimodal imaging approach for comprehensive assessment of retinoblastoma tumors in clinical trials.

Minimally disseminated disease and outcome in overt orbital retinoblastoma.

In this retrospective study of patients with overt orbital retinoblastoma, we evaluated minimally disseminated disease (MDD) in bone marrow and cerebrospinal fluid (CSF) using CRX and/or GD2 synthase as markers. Ten patients were evaluated-five (50%) at diagnosis and five upon relapse. MDD was detected in four cases (one in the bone marrow, two in the CSF, and in one case in both sites). All patients received chemotherapy and four received orbital radiotherapy. Seven patients relapsed or progressed and all of them died. Three patients remain in complete remission. There was no apparent correlation between MDD and the outcome.

Outcome of pediatric non-Hodgkin lymphoma in Central America: A report of the Association of Pediatric Hematology Oncology of Central America (AHOPCA).

BACKGROUND: Treating B-non-Hodgkin lymphoma (B-NHL) in lower-income countries is challenging because of imprecise diagnosis, the increased risk of fatal toxicity associated with advanced disease at presentation, and limited supportive care. PROCEDURE: Central American patients with newly diagnosed stage I or II B-NHL received a modified Berlin-Frankfurt-Münster (BFM) regimen including a prephase (prednisone, cyclophosphamide) followed by A/B/A courses (A: cytarabine, dexamethasone, etoposide, ifosfamide, methotrexate, and intrathecal therapy; B: cyclophosphamide, dexamethasone, doxorubicin, methotrexate, and intrathecal therapy). Those with stage III or IV NHL received additional courses (B/A/B), intensified for stage IV disease by additional vincristine and methotrexate doses. Patients in poor condition received a second prephase treatment before their chemotherapy courses. RESULTS: Between March 2004 and June 2016, of 405 patients with B-NHL, 386 (109 females) were eligible for treatment. Immunohistochemistry was performed in 177 cases (47.4%) and characterized the disease as mature B-cell lymphoma. Stage distribution was as follows: I/II, 31 (8.1%); III, 252 (65.3%); IV, 93 (24.1%); 10 (2.6%) not available. The 3-year overall survival was 70% for the whole group (86% for stages I/II, 75% for stage III, 58% for stage IV). Events included death during induction (34 patients, 8.8%), relapse/progression (46, 11.9%), death in remission (9, 2.3%), second malignancy (1, 0.26%), and death of unknown cause (1, 0.26%). Twenty-three (6%) patients abandoned or refused therapy. CONCLUSIONS: Approximately 70% of children with B-NHL from Central America experienced long-term, disease-free survival with a modified BFM schedule. Toxic death and relapse/resistant disease were the main reasons for treatment failure.

Feasibility and results of an intraarterial chemotherapy program for the conservative treatment of retinoblastoma in Argentina.

BACKGROUND: The feasibility and results of intraarterial chemotherapy, also termed ophthalmic artery chemosurgery (OAC), for retinoblastoma in less developed countries have seldom been reported. PROCEDURE: A retrospective evaluation of a program of OAC in Argentina from 2010 to 2015. RESULTS: Ninety-seven eyes from 81 patients (61 bilateral) were analyzed. In 35 eyes, OAC was given as primary therapy and in 62 it was used for the treatment of tumors with partial response or those relapsing after systemic chemoreduction with focal therapy or external-beam radiotherapy. Twenty-two primarily treated eyes had group D and 13 groups B/C. A total of 400 procedures were carried out. Chemotherapy used included combinations of melphalan, carboplatin, and topotecan. There was no mortality associated with OAC. Toxicity included fever and neutropenia in five (1.25%), hypotension and bradycardia during anesthesia in two and femoral thrombosis in one, eyelid edema in nine, and neutropenia or thrombocytopenia in 28 cycles. With a median follow-up of 48.7 months (range 12-79), the 3-year probability of event-free survival (pEFS) (enucleation and/or radiotherapy were considered events) was comparable for patients who received first-line therapy and those treated at relapse (0.65 vs. 0.63, P = 0.5). In the former, the pEFS was 0.91 and 0.43 for groups B/C and D, respectively (P = 0.01). Two patients died of extraocular dissemination after refusal of enucleation. CONCLUSIONS: OAC was feasible with low toxicity. pEFS improved in all groups compared to the previous experience with systemic chemotherapy reducing the use of radiotherapy. The overall mortality associated with OAC is comparable to our previous experience with systemic chemoreduction.

Second Neoplasms in Children Following a Treatment for Acute Leukemia and/or Lymphoma: 29 Years of Experience in a Single Institution in Argentina.

INTRODUCTION: Childhood acute leukemias (AL) and lymphomas achieve good survival rates. However, second neoplasms (SN) are a devastating event. METHODS: From August 1987 to December 2016, 34 of 3321 (1%) patients with diagnosis of AL or lymphoma developed SN. SN were AL (n=16), CNS tumors (n=5), endocrinal tumors (n=3), lymphomas (n=2), schwannoma (n=2) assorted sarcomas (n=4), retinal melanoma (n=1), and Vanek tumor (n=1). Median latency was 51 (range, 10 to 110) months for hematological malignancies and 119 (range, 25 to 236) months for solid tumors (P=0.001). RESULTS: A total of 33 patients with SN were treated taking into account cumulative doses of anthracyclines and radiotherapy. Twenty-three (67.6%) patients achieved complete remission (CR), 5 died early during therapy and 5 were refractory or partial responders. Six patients presented relapses of the SN and 1 died in CR. Seventeen patients remain alive in CR, with a median follow-up of 110 (range, 4 to 276) months. CONCLUSIONS: (1) The latency period was significantly longer for patients developing solid tumors than for those developing AL. (2) AL was the most frequent SN. (3) Our results strongly encourage giving standard therapy to SN, considering cumulative doses of previous treatment, since similar probabilities of surviving as "de novo" counterparts can be achieved.

OCULAR PHARMACOLOGY OF CHEMOTHERAPY FOR RETINOBLASTOMA.

PURPOSE: To review preclinical and clinical pharmacokinetic studies of the three most important chemotherapy drugs used for intraocular retinoblastoma and the contribution of the reported results to optimize treatment. METHODS: Systemic review of pharmacokinetic studies identified by a literature search at Pubmed using the keywords carboplatin, melphalan, topotecan, intravitreal, ophthalmic artery chemosurgery, pharmacokinetics, and retinoblastoma. RESULTS: A total of 21 studies were reviewed for assessing the preclinical and clinical pharmacokinetics of carboplatin, topotecan, and melphalan delivered by intravenous, periocular, ophthalmic artery, and intravitreal routes. Some preclinical studies were done before translation to the clinics. Others, despite encouraging preclinical data as reported for periocular topotecan did not correlate with clinical use. In addition, as was the case for melphalan after ophthalmic artery chemosurgery and despite nonfavorable preclinical information, some routes of drug delivery are clinically effective. Besides topotecan, complete knowledge of the pharmacokinetics of melphalan and carboplatin is still lacking. CONCLUSION: Pharmacokinetic knowledge of chemotherapy may aid to guide retinoblastoma treatment in favor of safety and efficacy. Nonetheless, results obtained in preclinical models should be translated with care to the clinics.

A Phase I Study of the Anti-Idiotype Vaccine Racotumomab in Neuroblastoma and Other Pediatric Refractory Malignancies.

BACKGROUND: Pediatric neuroectodermal malignancies express N-glycolylated gangliosides including N-glycolyl GM3 (NeuGcGM3) as targets for immunotherapy. PROCEDURE: We evaluated the toxicity and maximum tolerated dose and immunological response of racotumomab, an anti-idiotype vaccine targeting NeuGcGM3 through a Phase I study enrolling children with relapsed or resistant tumors expressing NeuGcGM3. MATERIALS AND METHODS: Drug dose was escalated to three levels (0.15-0.25-0.4 mg) of racotumomab administered intradermally. Each drug level included three patients receiving a total of three doses, every 14 days. A confirmation cohort was added to the highest dose level. Antibody response was assessed upon study entry and at 4-week intervals for at least three immunological determinations for each patient. RESULTS: Fourteen patients were enrolled (10 with neuroblastoma, one with retinoblastoma, one with Wilms' tumor, and two with brainstem glioma). Three patients completed the three drug levels and three were enrolled in the confirmation cohort. One patient died of tumor progression before completing the three applications. Racotumomab was well tolerated. The only side effect observed was grade 1-2 toxicity at the injection site. Racotumomab elicited an IgM and/or IgG antibody response directed against NGcGM3 in nine patients and IgM against racotumomab in 11 of 13 evaluable patients. The maximum tolerated dose was not reached and no dose-limiting toxicity was seen. CONCLUSIONS: Racotumomab vaccination has a favorable toxicity profile up to a dose of 0.4 mg, and most patients elicited an immune response. Its activity as immunotherapy for neuroectodermal malignancies will be tested in further clinical trials.

Clinical pharmacokinetics of intra-arterial melphalan and topotecan combination in patients with retinoblastoma.

PURPOSE: To assess the antitumor activity, toxicity, and plasma pharmacokinetics of the combination of melphalan and topotecan for superselective ophthalmic artery infusion (SSOAI) treatment of children with retinoblastoma. DESIGN: Single-center, prospective, clinical pharmacokinetic study. PARTICIPANTS: Twenty-six patients (27 eyes) with intraocular retinoblastoma. METHODS: Patients with an indication for SSOAI received melphalan (3-6 mg) and topotecan (0.5-1 mg; doses calculated by age and weight). Plasma samples were obtained for pharmacokinetic studies, and a population approach via nonlinear mixed effects modeling was used. Safety and efficacy were assessed and compared with historical cohorts of patients treated with melphalan single-agent SSOAI. MAIN OUTCOME MEASURES: Melphalan and topotecan pharmacokinetic parameters and efficacy and safety parameters. RESULTS: Twenty-seven eyes from 26 consecutive patients received 66 cycles of SSOAI melphalan and topotecan in combination. All 5 eyes treated as primary therapy responded to the combination chemotherapy and were preserved. Sixteen of the 22 eyes with relapsed or resistant tumors responded, but 3 of them ultimately underwent enucleation at a median of 8 months (range, 7.9-9.1 months). The incidence of grade III and IV neutropenia was 10.6% and 1.5%, respectively, which was comparable with historical controls of single-agent SSOAI melphalan. No episode of fever neutropenia was observed, and no patient required transfusion of blood products. The large variability in melphalan pharmacokinetics was explained by body weight (P <0.05). Concomitant topotecan administration did not influence melphalan pharmacokinetic parameters. There was no effect of the sequence of melphalan and topotecan administration in plasma pharmacokinetics. CONCLUSIONS: A regimen combining melphalan and topotecan for SSOAI treatment of retinoblastoma is active and well tolerated. This combination chemotherapy previously showed synergistic pharmacologic activity, and we herein provide evidence of not increasing the hematologic toxicity compared with single-agent melphalan.

Local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma: a preclinical and clinical study.

PURPOSE: Intravitreal melphalan is emerging as an effective treatment for refractory vitreous seeds in retinoblastoma, but there is limited understanding regarding its toxicity. This study evaluates the retinal and systemic toxicity of intravitreal melphalan in retinoblastoma patients, with preclinical validation in a rabbit model. DESIGN: Clinical and preclinical, prospective, cohort study. PARTICIPANTS: In the clinical study, 16 patient eyes received 107 intravitreal injections of 30 µg melphalan given weekly, a median of 6.5 times (range, 5-8). In the animal study, 12 New Zealand/Dutch Belt pigmented rabbits were given 3 weekly injections of 15 µg of intravitreal melphalan or vehicle to the right eye. METHODS: Electroretinogram (ERG) responses were recorded in both humans and rabbits. For the clinical study, ERG responses were recorded at baseline, immediately before each injection, and at each follow-up visit; 82 of these studies were deemed evaluable. Median follow-up time was 5.2 months (range, 1-11). Complete blood counts (CBCs) were obtained on the day of injection at 46 patient visits. In the animal study, ERG responses were obtained along with fluorescein angiography, CBCs, and melphalan plasma concentration. After humane killing, the histopathology of the eyes was evaluated. MAIN OUTCOME MEASURES: For the clinical study, we measured peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation with comparisons between ERG studies before and after intravitreal melphalan. For the animal study, we collected ERG parameters before and after intravitreal melphalan injections with histopathologic findings. RESULTS: By linear regression analysis, over the course of weekly intravitreal injections in retinoblastoma patients, for every additional injection, the ERG amplitude decreased by approximately 5.8 µV. The ERG remained stable once the treatment course was completed. In retinoblastoma patients, there were no grade 3 or 4 hematologic events. One week after the second injection in rabbits, the a- and b-wave amplitude declined significantly in the melphalan treated eyes compared with vehicle-treated eyes (P<0.05). Histopathology revealed severely atrophic retina. CONCLUSIONS: Weekly injections of 30 µg of melphalan can result in a decreased ERG response, which is indicative of retinal toxicity. These findings are confirmed at an equivalent dose in rabbit eyes by ERG measurements and by histopathologic evidence of severe retinal damage. Systemic toxicity with intravitreal melphalan at these doses in humans or rabbits was not detected.

Impact of chemoreduction for conservative therapy for retinoblastoma in Argentina.

BACKGROUND: Few studies were reported from developing countries regarding patient outcome and ocular survival in children with bilateral retinoblastoma treated with chemoreduction compared to external beam radiotherapy (EBRT). PROCEDURE: We undertook a retrospective study of three treatment eras: (1) (1988-1995) n = 68 when EBRT was used as primary conservative therapy; (2) (1995-2003) n = 46 when carboplatin-based systemic chemoreduction was introduced and (3) (2003-2009) (n = 83) when additional periocular chemotherapy was added for advanced tumors and pre-enucleation chemotherapy was given for those with massive buphthalmia. RESULTS: The probability of 5-year disease-free survival was 0.94 (95% confidence interval [CI] 0.91-0.98%) without significant differences among the three eras. Chemoreduction reduced the use of EBRT from 84.6% to 68.7% in eras 1 and 3, respectively (P = 0.008), which was more evident in cases with less advanced disease. Chemoreduction also significantly improved the 5-year probability of preservation of eyes with advanced disease from 0.13 (95% CI 0.04-0.27) during era 1 to 0.49 (95% CI 0.34-0.62) in era 3 (P < 0.0001). Chemoreduction was not associated with changes in the probability of extraocular relapse, which was reduced after the introduction of pre-enucleation chemotherapy. Second malignancies occurred in nine cases, acute myeloid leukemia being the most fatal one. Trilateral retinoblastoma occurred in three cases and all of them had been exposed to chemotherapy. CONCLUSIONS: Chemoreduction reduced the need for EBRT in eyes with less advanced disease and improved the preservation of eyes with advanced disease while its effects on secondary malignancies or trilateral disease remain unclear.