Monika L. Metzger

Treating Childhood Acute Lymphoblastic Leukemia without Cranial Irradiation

BACKGROUND Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse. METHODS We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it. RESULTS The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection. CONCLUSIONS With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.)

Management of occlusion and thrombosis associated with long-term indwelling central venous catheters

Long-term central venous catheters (CVCs) are important instruments in the care of patients with chronic illnesses, but catheter occlusions and catheter-related thromboses are common complications that can result from their use. In this Review, we summarise management of these complications. Mechanical CVC occlusions need cause-specific treatment, whereas thrombotic occlusions usually resolve with thrombolytic treatment, such as alteplase. Prophylaxis with thrombolytic flushes might prevent CVC infections and catheter-related thromboses, but confirmatory studies and cost-effectiveness analysis of this approach are needed. Risk factors for catheter-related thromboses include previous catheter infections, malposition of the catheter tip, and prothrombotic states. Catheter-related thromboses can lead to catheter infection, pulmonary embolism, and post-thrombotic syndrome. Catheter-related thromboses are usually diagnosed by Doppler ultrasonography or venography and treated with anticoagulation therapy for 6 weeks to a year, dependent on the extent of the thrombus, response to initial therapy, and whether thrombophilic factors persist. Prevention of catheter-related thromboses includes proper positioning of the CVC and prevention of infections; anticoagulation prophylaxis is not currently recommended.

Childhood cancer epidemiology in low‐income countries

Global studies of childhood cancer provide clues to cancer etiology, facilitate prevention and early diagnosis, identify biologic differences, improve survival rates in low‐income countries (LIC) by facilitating quality improvement initiatives, and improve outcomes in high‐income countries (HIC) through studies of tumor biology and collaborative clinical trials. Incidence rates of cancer differ between various ethnic groups within a single country and between various countries with similar ethnic compositions. Such differences may be the result of genetic predisposition, early or delayed exposure to infectious diseases, and other environmental factors. The reported incidence of childhood leukemia is lower in LIC than in more prosperous countries. Registration of childhood leukemia requires recognition of symptoms, rapid access to primary and tertiary medical care (a pediatric cancer unit), a correct diagnosis, and a data management infrastructure. In LIC, where these services are lacking, some children with leukemia may die before diagnosis and registration. In this environment, epidemiologic studies would seem to be an unaffordable luxury, but in reality represent a key element for progress. Hospital‐based registries are both feasible and essential in LIC, and can be developed using available training programs for data managers and the free online Pediatric Oncology Networked Data Base (www.POND4kids.org), which allows collection, analysis, and sharing of data. Cancer 2008.

Screening Adult Survivors of Childhood Cancer for Cardiomyopathy: Comparison of Echocardiography and Cardiac Magnetic Resonance Imaging

PURPOSE To compare two-dimensional (2D) echocardiography, the current method of screening for treatment-related cardiomyopathy recommended by the Childrens Oncology Group Guidelines, to cardiac magnetic resonance (CMR) imaging, the reference standard for left ventricular (LV) function. PATIENTS AND METHODS Cross-sectional, contemporaneous evaluation of LV structure and function by 2D and three-dimensional (3D) echocardiography and CMR imaging in 114 adult survivors of childhood cancer currently median age 39 years (range, 22 to 53 years) exposed to anthracycline chemotherapy and/or chest-directed radiation therapy. RESULTS In this survivor population, 14% (n = 16) had an ejection fraction (EF) less than 50% by CMR. Survivors previously undiagnosed with cardiotoxicity (n = 108) had a high prevalence of EF (32%) and cardiac mass (48%) that were more than two standard deviations below the mean of normative CMR data. 2D echocardiography overestimated the mean EF of this population by 5%. Compared with CMR, 2D echocardiography (biplane method) had a sensitivity of 25% and a false-negative rate of 75% for detection of EF less than 50%, although 3D echocardiography had 53% and 47%, respectively. Twelve survivors (11%) had an EF less than 50% by CMR but were misclassified as ≥ 50% (range, 50% to 68%) by 2D echocardiography (biplane method). Detection of cardiomyopathy was improved (sensitivity, 75%) by using a higher 2D echocardiography cutoff (EF < 60%) to detect an EF less than 50% by the reference standard CMR. CONCLUSION CMR identified a high prevalence of cardiomyopathy among adult survivors previously undiagnosed with cardiac disease. 2D echocardiography demonstrated limited screening performance. In this high-risk population, survivors with an EF 50% to 59% by 2D echocardiography should be considered for comprehensive cardiac assessment, which may include CMR.

Outcome of childhood acute lymphoblastic leukaemia in resource-poor countries

The causes of treatment failure in childhood acute lymphoblastic leukaemia are thought to differ between resource-rich and resource-poor countries. We assessed the records of 168 patients treated for this disease in Honduras. Abandonment of treatment (n=38), the main cause of failure, was associated with prolonged travel time to the treatment facility (2-5 h: hazard ratio 3.1, 95% CI 1.2-8.1 vs >5 h: 3.7, 1.3-10.9) and age younger than 4.5 years (2.6, 1.1-6.3). 35 patients died of treatment-related effects. Outcome could be substantially improved by interventions that help to prevent abandonment of therapy (such as funding for transport, satellite clinics, and support groups), and by prompt treatment of infection.

Male Reproductive Health After Childhood, Adolescent, and Young Adult Cancers: A Report From the Children's Oncology Group

The majority of children, adolescents, and young adults diagnosed with cancer will become long-term survivors. Although cancer therapy is associated with many adverse effects, one of the primary concerns of young male cancer survivors is reproductive health. Future fertility is often the focus of concern; however, it must be recognized that all aspects of male health, including pubertal development, testosterone production, and sexual function, can be impaired by cancer therapy. Although pretreatment strategies to preserve reproductive health have been beneficial to some male patients, many survivors remain at risk for long-term reproductive complications. Understanding risk factors and monitoring the reproductive health of young male survivors are important aspects of follow-up care. The Childrens Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer (COG-LTFU Guidelines) were created by the COG to provide recommendations for follow-up care of survivors at risk for long-term complications. The male health task force of the COG-LTFU Guidelines, composed of pediatric oncologists, endocrinologists, nurse practitioners, a urologist, and a radiation oncologist, is responsible for updating the COG-LTFU Guidelines every 2 years based on literature review and expert consensus. This review summarizes current task force recommendations for the assessment and management of male reproductive complications after treatment for childhood, adolescent, and young adult cancers. Issues related to male health that are being investigated, but currently not included in the COG-LTFU Guidelines, are also discussed. Ongoing investigation will inform future COG-LTFU Guideline recommendations for follow-up care to improve health and quality of life for male survivors.

Improved Prognosis for Older Adolescents With Acute Lymphoblastic Leukemia

PURPOSE The prognosis for older adolescents and young adults with acute lymphoblastic leukemia (ALL) has been historically much worse than that for younger patients. We reviewed the outcome of older adolescents (age 15 to 18 years) treated in four consecutive Total Therapy studies to determine if recent improved treatment extended to this high-risk group. PATIENTS AND METHODS Between 1991 and 2007, 963 pediatric patients, including 89 older adolescents, were enrolled on Total Therapy studies XIIIA, XIIIB, XIV, and XV. In the first three studies, treatment selection was based on presenting clinical features and leukemic cell genetics. In study XV, the level of residual disease was used to guide treatment, which featured intensive methotrexate, glucocorticoid, vincristine, and asparaginase, as well as early triple intrathecal therapy for higher-risk ALL. RESULTS The 89 older adolescents were significantly more likely to have T-cell ALL, the t(4;11)(MLL-AF4), and detectable minimal residual disease during or at the end of remission induction; they were less likely to have the t(12;21)(ETV6-RUNX1) compared with younger patients. In the first three studies, the 44 older adolescents had significantly poorer event-free survival and overall survival than the 403 younger patients. This gap in prognosis was abolished in study XV: event-free survival rates at 5 years were 86.4% ± 5.2% (standard error) for the 45 older adolescents and 87.4% ± 1.7% for the 453 younger patients; overall survival rates were 87.9% ± 5.1% versus 94.1% ± 1.2%, respectively. CONCLUSION Most older adolescents with ALL can be cured with risk-adjusted intensive chemotherapy without stem-cell transplantation.

Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study

BACKGROUND Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer. METHODS We did semen analysis on 214 adult male survivors of childhood cancer (median age 7·7 years [range 0·01-20·3] at diagnosis, 29·0 years [18·4-56·1] at assessment, and a median of 21·0 years [10·5-41·6] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling. FINDINGS Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration ≥15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m(2) were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=-0·37, p<0·0001). Mean CED was 10 830 mg/m(2) (SD 7274) in patients with azoospermia, 8480 mg/m(2) (4264) in patients with oligospermia, and 6626 mg/m(2) (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m(2) CED for azoospermia (OR 1·22, 95% CI 1·11-1·34), and for oligospermia (1·14, 1·04-1·25), but age at diagnosis and age at assessment were not. INTERPRETATION Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m(2). Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia, oligospermia, and azoospermia. These data can inform pretreatment patient counselling and use of fertility preservation services. FUNDING US National Cancer Institute, American Lebanese Syrian Associated Charities.

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

ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy.

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.