Catherine G. Lam

Rapamycin (sirolimus) in tuberous sclerosis associated pediatric central nervous system tumors.

Tuberous sclerosis complex (TSC) is associated with hamartomatous growths including subependymal giant cell astrocytomas (SEGAs). Since chemo‐radiation therapies offer scant benefit, oncologists had traditionally been little involved in managing SEGAs. Recent evidence demonstrating rapamycin efficacy in adults and children with TSC‐associated tumors foresee a practice change. We summarize our institutional experience and literature review that highlight potential benefits and hazards of rapamycin therapy, for TSC patients with SEGA, and other syndromal brain tumors. Pediatr Blood Cancer 2010;54:476–479.

The magnitude and predictors of abandonment of therapy in paediatric acute leukaemia in middle-income countries: A systematic review and meta-analysis

BACKGROUND Abandonment of therapy is a significant cause of paediatric cancer treatment failure in low- to middle-income countries (LMIC), but its impact has been underestimated. We performed a meta-analysis to determine the magnitude of abandonment in paediatric leukaemia in LMIC and sought to identify patient-, centre- and country-specific predictors of abandonment. PATIENTS AND METHODS We searched seven databases to identify paediatric oncology cohorts followed up from diagnosis and treated in LMIC. All languages were included. Two reviewers independently selected articles and extracted data. Authors were contacted for additional information. Subgroup analyses were planned a priori. RESULTS Of 22,384 publications, 318 in eight languages met criteria for full text review. 157 studies met analysis inclusion criteria. Abandonment rates (ARs), obtained for 83 of the 157 studies (52.9%), ranged from 0% to 74.5%. ARs were frequently unreported and available only directly from authors. Forty studies (10,494 children in 20 countries) were quantitatively analysed. ARs for acute lymphoblastic laeukemia in lower-middle-income countries (lower-MICs) were higher than in upper-middle-income countries (29%, 95% confidence interval (CI) 23-36% versus 2%, 95% CI 1-3%; p<0.0001) but were heterogeneous (I(2)=98%; p<0.0001). This heterogeneity was not explained by centre-specific (free versus paid treatment) or country-specific (government health expenditure, per-capital income) subgroups. CONCLUSIONS In LMICs, ARs are highest in lower-MICs. However, their broad range suggests that low ARs are possible in resource-constrained settings. Analysis of outliers may suggest interventions for use at other centres. Methodologically appropriate reporting of ARs should be adopted. Future research should evaluate interventions targeting abandonment.

Magnitude of Treatment Abandonment in Childhood Cancer

Background Treatment abandonment (TxA) is recognized as a leading cause of treatment failure for children with cancer in low-and-middle-income countries (LMC). However, its global frequency and burden have remained elusive due to lack of global data. This study aimed to obtain an estimate using survey and population data. Methods Childhood cancer clinicians (medical oncologists, surgeons, and radiation therapists), nurses, social workers, and psychologists involved in care of children with cancer were approached through an online survey February-May 2012. Incidence and population data were obtained from public sources. Descriptive, univariable, and multivariable analyses were conducted. Results 602 responses from 101 countries were obtained from physicians (84%), practicing pediatric hematology/oncology (83%) in general or children’s hospitals (79%). Results suggested, 23,854 (15%) of 155,088 children <15 years old newly diagnosed with cancer annually in the countries analyzed, abandon therapy. Importantly, 83% of new childhood cancer cases and 99% of TxA were attributable to LMC. The annual number of cases of TxA expected in LMC worldwide (26,166) was nearly equivalent to the annual number of cancer cases in children <15 years expected in HIC (26,368). Approximately two thirds of LMC had median TxA≥6%, but TxA ≥6% was reported in high- (9%), upper-middle- (41%), lower-middle- (80%), and low-income countries (90%, p<0.001). Most LMC centers reporting TxA>6% were outside the capital. Lower national income category, higher reliance on out-of-pocket payments, and high prevalence of economic hardship at the center were independent contextual predictors for TxA ≥6% (p<0.001). Global survival data available for more developed and less developed regions suggests TxA may account for at least a third of the survival gap between HIC and LMC. Conclusion Results show TxA is prevalent (compromising cancer survival for 1 in 7 children globally), confirm the suspected high burden of TxA in LMC, and illustrate the negative impact of poverty on its occurrence. The present estimates may appear small compared to the global burden of child death from malnutrition and infection (measured in millions). However, absolute numbers suggest the burden of TxA in LMC is nearly equivalent to annually losing all kids diagnosed with cancer in HIC just to TxA, without even considering deaths from disease progression, relapse or toxicity–the main causes of childhood cancer mortality in HIC. Results document the importance of monitoring and addressing TxA as part of childhood cancer outcomes in at-risk settings.

Nimotuzumab in pediatric glioma

High-grade gliomas and diffuse brainstem gliomas carry a very poor prognosis despite current therapies, and account together for the largest number of deaths in children with brain tumors. Many of these tumors have been found to overexpress the EGF receptor (EGFR). Nimotuzumab (h-R3) is a humanized monoclonal antibody against the EGFR, and consequently inhibits tyrosine kinase activation. In vitro and in vivo studies have supported the antiproliferative, antiangiogenic, pro-apoptotic and radiosensitizing activities of nimotuzumab. Emerging trials suggest a promising role for nimotuzumab as a therapeutic agent in patients with high-grade gliomas. This review attempts to provide a context for the evolving interest and evidence for nimotuzumab in pediatric glioma.

Interventions targeting absences increase adherence and reduce abandonment of childhood cancer treatment in El Salvador

In El Salvador, about 200 new cases of pediatric cancer are diagnosed each year, and survival rates approach 70%. Although treatment is available at no cost, abandonment of therapy has remained at a steady yearly rate of 13% during the past decade. A time sensitive adherence tracking procedure (TS‐ATP) was recently implemented to detect missed appointments, identify their causes, and intervene promptly.

SIOP‐PODC adapted risk stratification and treatment guidelines: Recommendations for neuroblastoma in low‐ and middle‐income settings

Neuroblastoma is the most common extracranial solid tumor in childhood in high‐income countries (HIC), where consistent treatment approaches based on clinical and tumor biological risk stratification have steadily improved outcomes. However, in low‐ and middle‐ income countries (LMIC), suboptimal diagnosis, risk stratification, and treatment may occur due to limited resources and unavailable infrastructure. The clinical practice guidelines outlined in this manuscript are based on current published evidence and expert opinions. Standard risk stratification and treatment explicitly adapted to graduated resource settings can improve outcomes for children with neuroblastoma by reducing preventable toxic death and relapse. Pediatr Blood Cancer 2015;62:1305–1316.

Reported Availability and Gaps of Pediatric Palliative Care in Low- and Middle-Income Countries: A Systematic Review of Published Data

BACKGROUND The majority of young people in need of palliative care live in low- and middle-income countries, where curative treatment is less available. OBJECTIVE We systematically reviewed published data describing palliative care services available to young people with life-limiting conditions in low- and middle-income countries and assessed core elements with respect to availability, gaps, and under-reported aspects. METHODS PubMed, CINAHL, EMBASE (1980-2013), and secondary bibliographies were searched for publications that included patients younger than 25 years with life-limiting conditions and described palliative care programs in low- and middle-income countries. A data extraction checklist considered 15 items across seven domains: access, education/capacity building, health system support, pain management, symptom management, end-of-life care, and bereavement. Data were aggregated by program and country. RESULTS Of 1572 records, 238 met criteria for full-text review; 34 qualified for inclusion, representing 30 programs in 21 countries. The median checklist score was 7 (range, 1-14) of 10 reported (range, 3-14). The most pervasive gaps were in national health system support (unavailable in 7 of 17 countries with programs reporting), specialized education (unavailable in 7 of 19 countries with programs reporting), and comprehensive opioid access (unavailable in 14 of 21 countries with programs reporting). Underreported elements included specified practices for pain management and end-of-life support. CONCLUSION Comprehensive pediatric palliative care provision is possible even in markedly impoverished settings. Improved national health system support, specialized training and opioid access are key targets for research and advocacy. Application of a checklist methodology can promote awareness of gaps to guide program evaluation, reporting, and strengthening.

Determinants of Treatment Abandonment in Childhood Cancer: Results from a Global Survey

Background Understanding and addressing treatment abandonment (TxA) is crucial for bridging the pediatric cancer survival gap between high-income (HIC) and low-and middle-income countries (LMC). In childhood cancer, TxA is defined as failure to start or complete curative cancer therapy and known to be a complex phenomenon. With rising interest on causes and consequences of TxA in LMC, this study aimed to establish the lay-of-the-land regarding determinants of TxA globally, perform and promote comparative research, and raise awareness on this subject. Methods Physicians (medical oncologists, surgeons, and radiation therapists), nurses, social workers, and psychologists involved in care of children with cancer were approached through an online survey February-May 2012. Queries addressed social, economic, and treatment-related determinants of TxA. Free-text comments were collected. Descriptive and qualitative analyses were performed. Appraisal of overall frequency, burden, and predictors of TxA has been reported separately. Results 581 responses from 101 countries were obtained (contact rate = 26%, cooperation rate = 70%). Most respondents were physicians (86%), practicing pediatric hematology/oncology (86%) for >10 years (54%). Providers from LMC considered social/economic factors (families’ low socioeconomic status, low education, and long travel time), as most influential in increasing risk of TxA. Treatment-related considerations such as preference for complementary and alternative medicine and concerns about treatment adverse effects and toxicity, were perceived to play an important role in both LMC and HIC. Perceived prognosis seemed to mediate the role of other determinants such as diagnosis and treatment phase on TxA risk. For example, high-risk of TxA was most frequently reported when prognosis clearly worsened (i.e. lack of response to therapy, relapse), or conversely when the patient appeared improved (i.e. induction completed, mass removed), as well as before aggressive/mutilating surgery. Provider responses allowed development of an expanded conceptual model of determinants of TxA; one which illustrates established and emerging individual, family, center, and context specific factors to be considered in order to tackle this problem. Emerging factors included vulnerability, family dynamics, perceptions, center capacity, public awareness, and governmental healthcare financing, among others. Conclusion TxA is a complex and multifactorial phenomenon. With increased recognition of the role of TxA on global pediatric cancer outcomes, factors beyond social/economic status and beliefs have emerged. Our results provide insights regarding the role of established determinants of TxA in different geographical and economic contexts, allow probing of key determinants by deliberating their mechanisms, and allow building an expanded conceptual model of established and emerging determinants TxA.

Interventions to improve adherence to treatment for paediatric tuberculosis in low- and middle-income countries: a systematic review and meta-analysis

Abstract Objective To assess the design, delivery and outcomes of interventions to improve adherence to treatment for paediatric tuberculosis in low- and middle-income countries and develop a contextual framework for such interventions. Methods We searched PubMed and Cochrane databases for reports published between 1 January 2003 and 1 December 2013 on interventions to improve adherence to treatment for tuberculosis that included patients younger than 20 years who lived in a low- or middle-income country. For potentially relevant articles that lacked paediatric outcomes, we contacted the authors of the studies. We assessed heterogeneity and risk of bias. To evaluate treatment success – i.e. the combination of treatment completion and cure – we performed random-effects meta-analysis. We identified areas of need for improved intervention practices. Findings We included 15 studies in 11 countries for the qualitative analysis and of these studies, 11 qualified for the meta-analysis – representing 1279 children. Of the interventions described in the 15 studies, two focused on education, one on psychosocial support, seven on care delivery, four on health systems and one on financial provisions. The children in intervention arms had higher rates of treatment success, compared with those in control groups (odds ratio: 3.02; 95% confidence interval: 2.19–4.15). Using the results of our analyses, we developed a framework around factors that promoted or threatened treatment completion. Conclusion Various interventions to improve adherence to treatment for paediatric tuberculosis appear both feasible and effective in low- and middle-income countries.

Hospital detention practices: statement of a global taskforce

Hospital detention practices can be defined as refusal to release living patients after medical discharge is clinically indicated, or refusal to release bodies of deceased patients, when families are unable to pay hospital bills. Each additional day for which patients are detained adds to their bills, increasingly hindering families’ ability to obtain patients’ release. Patients are sometimes detained in hospitals, or bodies detained in mortuaries, for months. Occasionally, patients are completely left behind in hospitals when families are unable to pay. Unclaimed patients’ bodies might be disposed of in mass graves. The problem’s magnitude is unknown, but is probably more widespread than is documented. Hospital detention has been reported by human rights organisations, clinicians, journalists, and laypeople in Africa, Asia, Latin America, and eastern Europe. The problem aff ects children and adults with acute disorders (eg, people involved in road accidents and women with birth complications) and chronic diseases (eg, cancer or HIV/AIDS). Reports do not have consistent terminology to enable comparisons of studies worldwide or to eff ectively unite forces. We have formed the International Society of Paediatric Oncology and Paediatric Oncology in Developing Countries (SIOP PODC) Global Taskforce on Hospital Detention Practices, with the following objectives: to augment critical awareness; to introduce consistent terminology; to help to map global scope reliably; to elucidate adverse consequences; to address root causes; and to identify and support implementation of eff ective solutions to end hospital detention practices. The Taskforce endorses the following core statements related to each objective. Patients’ detention violates international human rights, including the right to not be imprisoned as a debtor and to have access to medical care. Recommended terminology includes “hospital detention practices” and “detained patients”. The term “detention” minimises confusion with positive health-care retention in medical literature. The term “practices” more accurately describes reality than does “policies”. Although hospital detention is often not the offi cial policy publicly defended by governments, it might be a wide spread unofficial practice. To map the global scope, the Taskforce calls on professionals and advocates to report hospital detention in scientifi c journals, media, and public venues. Recognition of adverse consequences is crucial. Fear of detention might prevent or delay conventional medical help-seeking, and encourages abandonment of potentially curative treatment after patients’ release. Progressive or relapsed disease and unnecessary death often result. Detention aggravates hospital overcrowding, increases infection risk, and denies schooling to children. Hospital detention is often the result of mismanagement, corruption, dysfunctional health-care system structures, inadequate health insurance coverage, and unfair waiver procedures, warranting attention. Advocacy by stakeholders is urgently needed (panel). Our Taskforce endorses this position statement in the conviction that detention of patients is unethical and inhumane, and must end.