Miguel Bonilla

Protocol-based treatment for children with cancer in low income countries in Latin America: A report on the recent meetings of the Monza International School of Pediatric Hematology/Oncology (MISPHO)—Part II

Pediatric cancer programs in low‐income countries (LIC) can improve outcomes. However, treatment must be tailored to the patients living conditions and the availability of supportive care. In some cases, a more intense regimen will decrease survival since the increase in death from toxicity may exceed any decrease in relapse. Attempts to practice evidence‐based pediatric oncology are thwarted by the lack of evidence derived from local experience in LIC to determine optimal therapy. This report summarizes treatment regimens used by pediatric oncologists from 15 countries of the Caribbean, Central and South America who participate in the Monza International School of Pediatric Hematology/Oncology (MISPHO). Patients with hepatoblastoma, Wilms tumor, and histiocytosis treated on unmodified published protocols had outcomes comparable to those in high‐income countries (HIC). Those with rhabdomyosarcoma, osteosarcoma, Hodgkin lymphoma, and acute myeloid leukemia treated with unmodified regimens had event‐free survival estimates 10%–20% lower than those reported in HIC due to higher rates of toxic death, abandonment of therapy, and relapse. Treatment of retinoblastoma is complicated by advanced stages and extraocular disease at diagnosis; improved outcomes depend on education of pediatricians and the public to recognize early signs of this disease. Use of unmodified protocols for Burkitt lymphoma and acute lymphoblastic leukemia have been associated with unacceptable toxicity in LIC, so MISPHO centers have modified published regimens by giving lower doses of methotrexate and reducing use of anthracyclines. Despite the use of all‐trans‐retinoic acid during induction for acute promyelocytic leukemia, the incidence of fatal hemorrhage remains unacceptably high. Pediatr Blood Cancer

Acute lymphoblastic leukemia in a developing country : Preliminary results of a nonrandomized clinical trial in El Salvador

Purpose To improve outcome and study biology of childhood acute lymphoblastic leukemia (ALL) in El Salvador. Patients and Methods Between January 1994 and December 1996, 153 children of El Salvador had newly diagnosed ALL treated in a collaborative program between Hospital Benjamin Bloom and St. Jude Childrens Research Hospital (SJCRH). Therapy was based on a modified SJCRH protocol, with uniform remission induction (prednisone, vincristine, L-asparaginase) followed-up by consolidation with teniposide/cytarabine and/or high-dose methotrexate. Continuation treatment was risk-stratified: 123 patients assigned to the high-risk group received weekly rotational drug pairs, and 16 assigned to the standard-risk group received daily 6-mercaptopurine, weekly methotrexate, and monthly pulses of vincristine plus dexamethasone. High risk was defined as: DNA index <1.16, age 12 months or younger, white blood cell count ≥ 50 × 109/L, T-cell immunophenotype, anterior mediastinal mass, central nervous system leukemia at diagnosis, or t(4;11), t(1;19), or t(9;22). Duration of the continuation treatment was 2.5 years in both groups. The median age at diagnosis of all patients was 4.8 (range 1 d–17 yrs), median leukocyte count was 15 (range 1–766) × 109/L, and sex distribution was equal. Results Immunophenotypes were early &bgr;-progenitor in 79%, T-cell in 3.9%, and inconclusive in 17% of cases. DNA index was <1.16 in 80.5% and was ≥1.16 in 19.5% of the 123 known cases. For the analyzes, patients who refused therapy (abandoned treatment) were considered to have treatment failure as of their last follow-up dates. Complete remission was achieved in 126 of 151 (82.4%) patients (11 abandoned therapy during induction). The overall 4-year event-free survival (EFS) rate ± 1 standard error was 48 ± 6%. The 4-year EFS rates in patients at high-risk and standard-risk were 46 ± 7% (n = 121) and 69 ± 15% (n = 16), respectively (P = 0.20). When patients who refused further treatment are censored, the corresponding 4-year estimates of EFS are 51 ± 8% and 75 ± 14%, respectively. Conclusions These results suggest that the biology of childhood ALL in El Salvador appears to be similar to that seen in the United States. Risk-directed chemotherapy can successfully be used in developing countries, but risk factors must be carefully determined and applied.

Nutritional status at diagnosis is related to clinical outcomes in children and adolescents with cancer: A perspective from Central America

BACKGROUND The prevalence of malnutrition in children may exceed 50% in countries with limited resources. The aims of this study were to assess nutritional status at diagnosis in children and adolescents with cancer, and to correlate it with clinical outcomes in the Spanish speaking countries of Central America that formed the AHOPCA (Asociacion de Hemato-Oncologia Pediatrica de Centro America) consortium. METHODS Patients aged 1-18 years, diagnosed with cancer between 1st October 2004 and 30th September 2007, were eligible for study. Weight (kg) and height or length (m), mid upper arm circumference--MUAC and triceps skin fold thickness--TSFT were measured and their Z-scores or percentiles were calculated. Three categories of nutritional status were defined according to these parameters. RESULTS A total of 2954 new patients were enrolled; 1787 had all anthropometric measurements performed and 1513 also had measurements of serum albumin. By arm anthropometry 322/1787 patients (18%) had moderate nutritional depletion and 813/1787 patients (45%) were severely depleted. Adding serum albumin, the proportion classified as severely depleted rose to 59%. Malnourished children more often abandoned therapy and their event free survival was inferior to that of other children. CONCLUSIONS Arm anthropometry in children with cancer is a sensitive measure of nutritional status. Since malnutrition at diagnosis was related to important clinical outcomes, an opportunity exists to devise simple, cost-effective nutritional interventions in such children that may enhance their prospects for survival.

Prevalence and predictors of abandonment of therapy among children with cancer in El Salvador

Abandonment of therapy is one of the most common causes of treatment failure among children with cancer in low‐income countries. Our objectives were to describe the prevalence and predictors of abandonment among such children with cancer in El Salvador. We analyzed data on patients younger than 16 years, diagnosed with any malignancy between January 2001 and December 2003 at the Benjamin Bloom National Childrens Hospital, San Salvador. Among 612 patients, 353 were male (58%); the median age at diagnosis was 5.1 years; 59% of patients were diagnosed with leukemia/lymphoma, 28% with solid tumors and 13% with brain tumors. The prevalence of abandonment was 13%. Median time to abandonment was 2.0 (range 0–36) months. In univariate analyses, paternal illiteracy [odds ratio (OR) 3.8, 95% confidence interval (CI) 2.0–7.2; p = 0.001]; maternal illiteracy (OR = 5.1, 95% CI 2.5–10; p < 0.0001); increasing number of household members (OR = 1.2, 95% CI 1.1–1.3; p = 0.004); and low monthly household income (OR per

Effect of malnutrition at the time of diagnosis on the survival of children treated for cancer in El Salvador and Northern Brazil.

100 = 0.59, 95% CI 0.45–0.75; p < 0.0001) all significantly increased the risk of abandonment, whereas travel time to hospital did not. In multiple regression analyses, low monthly income and increased number of people in the household were independently predictive of abandonment. In conclusion, in El Salvador, despite the provision of free treatment, socioeconomic variables significantly predict increased risk of abandonment of therapy. Understanding the pathways through which socioeconomic status affects abandonment may allow the design of effective interventions.

Asociación de Hemato-Oncología Pediátrica de Centro América (AHOPCA): a model for sustainable development in pediatric oncology.

Purpose To investigate the relationship between survival and malnutrition at the time of diagnosis among children treated for cancer in two developing countries. Patients and Methods We studied 443 children treated for cancer between 1995 and 1998 at two centers in San Salvador, El Salvador, and Recife, Brazil. Median age at diagnosis was 4.9 years; 283 children had leukemia and 160 had solid tumors. Z-scores were calculated for weight for age (WAZ), height for age (HAZ), and weight for height (WHZ) at diagnosis. Z scores <−2 indicated malnutrition. Patients were also stratified by low-risk disease (solid tumors: stage I, stage II, or localized; acute lymphocytic leukemia: white blood cell count <25,000/&mgr;L, no central nervous system involvement, no mediastinal mass and age >1 and <10 yrs) and high-risk disease (all other patients, including those with acute or chronic myelocytic leukemia). Results Z-scores indicated malnutrition in 23.5% (WAZ), 22.8% (HAZ), and 15.7% (WHZ) of patients. Z-score was not significantly related to overall survival rates, to survival rates analyzed by type of malignancy or risk status, or to survival rates at the end of the first month of treatment. Conclusions We found no relationship between nutritional status and survival in these patients. This implies that future protocols for use in developing countries can be designed to provide optimal treatment intensity despite the high incidence of malnutrition.

Treatment‐related mortality in children with acute lymphoblastic leukemia in Central America

Bridging the survival gap for children with cancer, between those (the great majority) in low and middle income countries (LMIC) and their economically advantaged counterparts, is a challenge that has been addressed by twinning institutions in high income countries with centers in LMIC. The long‐established partnership between a Central American consortium—Asociación de Hemato‐Oncología Pediátrica de Centro América (AHOPCA)—and institutions in Europe and North America provides a striking example of such a twinning program. The demonstrable success of this endeavor offers a model for improving the health outcomes of children with cancer worldwide. As this remarkable enterprise celebrates its 15th anniversary, it is appropriate to reflect on its origin, subsequent growth and development, and the lessons it provides for others embarking on or already engaged in similar journeys. Many challenges have been encountered and not all yet overcome. Commitment to the endeavor, collaboration in its achievements and determination to overcome obstacles collectively are the hallmarks that stamp AHOPCA as a particularly successful partnership in advancing pediatric oncology in the developing world. Pediatr Blood Cancer 2014;61:345–354.

AMOR: A proposed cooperative effort to improve outcomes of childhood cancer in Central America

The objectives of this study were to describe the incidence, timing, and predictors of treatment‐related mortality (TRM) among children with acute lymphoblastic leukemia (ALL) in El Salvador, Guatemala, and Honduras.

Incidence and predictors of treatment-related mortality in paediatric acute leukaemia in El Salvador

The dramatic reduction of pediatric cancer mortality rates has been one of the greatest accomplishments of contemporary medicine. About 80% of children with cancer are now expected to be cured by current therapies. However, most of the worlds children have no access to cancer treatment. The translation of effective pediatric cancer therapies to impoverished regions of the world presents an enormous challenge to the health care profession. Over the past 20 years, efforts have been under way to extend adequate cancer treatment to an increasing number of children in developing countries. These initiatives, collectively designated “twinning programs,” consist essentially of a partnership between a pediatric cancer unit in a developing country and a group of health care providers in the developed world. Here we review the twinning programs that have been implemented in Central America, discuss their impact on the development of local resources and the outcome of childhood cancer, and propose a collaborative research initiative aimed at improving the international dissemination of progress in pediatric hematology‐oncology.

Development of retinoblastoma programs in Central America

Survival rates among children with leukaemia in low-income countries are lower than those in high-income countries. This has been attributed in part to higher treatment-related mortality (TRM). We examined the demographics, treatment, and outcomes of paediatric patients in El Salvador with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) to determine the incidence, causes, and risk factors for TRM. Two trained data managers collected data prospectively; no patients were excluded. Biological, socioeconomic and nutritional predictors were examined. A total of 469 patients with ALL and 78 patients with AML were included. The 2-year cumulative incidence of TRM was significantly higher among children with AML (35.4±6.4%) than those with ALL (12.5±1.7%; P<0.0001). However, the proportion of deaths attributable to the toxicity of treatment did not differ significantly between AML (25/47, 53.2%) and ALL (55/107, 51.4%; P=0.98). Among children with ALL, low monthly income (P=0.04) and low parental education (P=0.02) significantly increased the risk of TRM. Among children with AML, biological, socioeconomic, and nutritional variables were not associated with TRM. In this low-income country, toxic death significantly contributes to mortality in both ALL and AML. A better understanding of the effect of socioeconomic status on TRM may suggest specific strategies for patients with ALL.