A questionnaire based review of long-term follow-up programs for survivors of childhood cancer in Canada

Background

Major advances have been made in the treatment of childhood cancer; however, survivors of childhood cancer are at increased risk for morbidity and mortality. There is little literature regarding available long‐term follow‐up programs for survivors of childhood cancer.

Procedure

In March 2007, 16 surveys were sent to pediatric hematology/oncology programs across Canada to determine what programs were available for survivors of childhood cancer, and the nature of such programs.

Results

Of 15 participating centers, 13 (87%) have multi‐disciplinary programs for the long‐term follow‐up of pediatric cancer survivors. Research databases were documented in 9/15 (60%) of centers to document late effects. Dedicated programs for adult survivors of childhood cancer were established in 8/15 (53%) of centers. Access to subspecialty care for survivors was rated as quite good. Concerns were raised by many participants about patients being lost to follow‐up. Respondents indicated that primary care physicians appear to be under‐represented within dedicated long‐term follow‐up programs.

Conclusion

Long‐term follow‐up programs for survivors of childhood cancer are available in 87% of Canadian pediatric oncology centers. While programs reported good access to care for childhood survivors, many adult survivors of childhood cancer have more limited timely access to services and patients are often lost to follow‐up. New models of care incorporating primary care physicians are necessary due to growing numbers of survivors. Pediatr Blood Cancer 2009;52:113–115. © 2008 Wiley‐Liss, Inc.     

Is postal follow‐up of childhood cancer survivors worthwhile?

Background

Childhood cancer survival has increased over the last 30 years, but long‐term effects necessitate continued monitoring of survivors. Since not all of them attend follow‐up clinics, this study assesses the efficacy of obtaining information from general practitioners (GPs) through a 5‐year rolling postal program.

Procedure

Survivors were included who had been diagnosed with a malignancy in the West Midlands since 1957 and were not attending central long‐term follow‐up clinics.

Results

One thousand twenty‐seven patients were followed up between 1993 and 2004. Replies were received on 903 (88% response). There were 44 subsequent malignancies and 42 deaths. No medical problems were reported in 341/935 patients (36.5%); in the other 594 endocrine effects were the most common, with visual effects the biggest single problem. Brain tumor survivors had the largest proportion of problems.

Conclusions

The response rate and information quality achieved show that this method of follow‐up is feasible, in cases of discharged or defaulting patients. These data will complement those derived from hospital‐based follow‐up studies, to give a broader understanding of the spectrum of late effects experienced by survivors and may inform the development of specific long‐term follow‐up protocols. Pediatr Blood Cancer 2008;50:80–84. © 2007 Wiley‐Liss, Inc.     

Survey of long‐term follow‐up programs in the United States for survivors of childhood brain tumors

Introduction

Despite recognition that childhood brain tumor survivors often suffer multiple late effects following therapy, little is known regarding the long‐term follow‐up (LTFU) programs for these patients.

Methods

A 16‐question survey was mailed to member institutions of the Children's Oncology Group in the United States. Institutions were asked about the size of their brain tumor program, activities of the LTFU programs and perceived barriers to follow‐up.

Results

One hundred forty‐five (74%) of 197 institutions returned surveys. Care for patients <21 years old at diagnosis who are >2 years following completion of therapy was provided at a designated neuro‐oncology LTFU clinic (31.2%), a general LTFU program for childhood cancer survivors (30.4%), or a general pediatric oncology program (29.7%). Institutions with a neuro‐oncology LTFU clinic were more likely to use neuro‐psychological testing following radiation therapy (P = 0.001), have longer duration of continued surveillance imaging (P = 0.02), use growth hormone replacement for medulloblastoma survivors (P < 0.001) and continue the use of growth hormone into adulthood (P = 0.05) than those with a general pediatric oncology program. Perceived barriers to care of brain tumor survivors included limited access and lack of insurance (32.1%), lack of funding or dedicated time for providers (22.9%), patients' uncertainty about need to follow‐up (20.6%), and patients' desire to not be followed in a pediatric cancer program (12.2%).

Conclusions

Considerable variation exists across institutions in the United States in the delivery of follow‐up care for survivors of childhood brain tumors. We encourage additional investigation to better define and implement optimal follow‐up care for childhood brain tumor survivors. Pediatr Blood Cancer 2009; 53:1295–1301. © 2009 Wiley‐Liss, Inc.     

Long‐term pulmonary disease among Swiss childhood cancer survivors

1 Background

Pulmonary diseases are potentially severe late complications of childhood cancer treatment that increase mortality risk among survivors. This nationwide study assesses the prevalence and incidence of pulmonary diseases in long‐term childhood cancer survivors (CCS) and their siblings, and quantifies treatment‐related risks.

2 Methods

As part of the Swiss Childhood Cancer Survivor Study, we studied CCS who were diagnosed between 1976 and 2005 and alive at least 5 years after diagnosis. We compared prevalence of self‐reported pulmonary diseases (pneumonia, chest wall abnormalities, lung fibrosis, emphysema) between CCS and their siblings, calculated cumulative incidence of pulmonary diseases using the Kaplan–Meier method, and determined risk factors using multivariable logistic regression.

3 Results

CCS reported more pneumonias (10% vs. 7%, P = 0.020) and chest wall abnormalities (2% vs. 0.4%, P = 0.003) than siblings. Treatment with busulfan was associated with prevalence of pneumonia (odds ratio [OR] 4.0, 95% confidence interval [CI] 1.1–14.9), and thoracic surgery was associated with chest wall abnormalities and lung fibrosis (OR 4.1, 95% CI 1.6–10.7 and OR 6.3, 95% CI 1.7–26.6). Cumulative incidence of any pulmonary disease after 35 years of follow‐up was 21%. For pneumonia, the highest cumulative incidence was seen in CCS treated with both pulmotoxic chemotherapy and radiotherapy to the thorax (23%).

4 Conclusion

This nationwide study in CCS found an increased risk for pulmonary diseases, especially pneumonia, while still young, which indicates that CCS need long‐term pulmonary follow‐up.     

Rapid and fulminant leptomeningeal spread following radiotherapy in diffuse intrinsic pontine glioma

A 4‐year‐old male presented with rapid‐onset cranial nerve palsy and ataxia. Brain magnetic resonance imaging (MRI) revealed a pontine mass lesion with discordant conventional and advanced imaging. A stereotactic core biopsy revealed glioblastoma with immunostaining suggestive of histone H3K27M and TP53 mutation, consistent with diffuse intrinsic pontine glioma. MRI 3 months after radiotherapy revealed extensive new leptomeningeal metastatic disease involving both the supra‐ and infratentorial brain, as well as the imaged portion of the spine. Tissue procured at the time of needle biopsy has undergone striking in vivo expansion as an orthotopic xenograft.     

Cortical surface area and thickness in adult survivors of pediatric acute lymphoblastic leukemia

Background

Advances in the treatment of acute lymphoblastic leukemia (ALL) have led to great improvements in survival rates and outcomes, but there is concern about cognitive late effects. We aimed to determine whether ALL survivors have smaller cortical surface area and/or thickness, and test whether this is related to disease and treatment variables and self‐reported executive functioning in everyday life.

Procedure

Magnetic resonance imaging (MRI) scans from 130 adult long‐term survivors of childhood ALL (age: 18–46 years; age at diagnosis: 0–16 years; years since diagnosis: 7–40) and 130 healthy controls were assessed to estimate and compare regional cortical surface area and thickness. Information on disease and treatment factors were obtained from patients’ records, and executive functioning in survivors was measured using a validated questionnaire (BRIEF‐A).

Results

Smaller cortical surface area was observed in several regions in both cerebral hemispheres in ALL survivors. In these regions, mean surface area was 4.1–5.5% smaller in ALL survivors compared to healthy controls. In contrast, only one region showed lower cortical thickness in ALL survivors. There were no significant associations between cortical surface area/thickness in these regions and disease or treatment variables. In ALL survivors, smaller surface area in prefrontal regions, encompassing parts of the superior frontal gyri and the left anterior cingulate cortex, was associated with problems in executive functioning, specifically with emotional control and self‐monitoring.

Conclusions

ALL survivors had smaller surface area in several cortical regions and smaller surface area in prefrontal regions was associated with reported problems in executive functioning. Pediatr Blood Cancer 2015;62:1027–1034. © 2015 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals, Inc.     

Metastatic Low‐Grade Gliomas in Children: 20 Years' Experience at St. Jude Children's Research Hospital

Background

Patients with low‐grade gliomas (LGG), which are the most common childhood brain tumors, have excellent long‐term survival. Dissemination of LGG is rare. Robust data on the incidence, presentation, patterns of dissemination, disease behavior, outcome, and best‐management approaches do not exist. We describe 20 years of follow‐up of children with metastatic LGG.

Procedure

Data collected during the period 1990–2010 were retrospectively reviewed for the following inclusion criteria: diagnosis of metastatic LGG, age younger than 21 years at initial diagnosis, and magnetic resonance imaging of the brain and/or spine at diagnosis and/or follow‐up. Patient demographics, pathology, treatment modalities, and outcome were reviewed.

Results

Of 599 patients with LGG, 38 (6%) had metastatic disease at either diagnosis or follow‐up. Most tumors (87%) were located in the brain, and half of the patients had metastatic disease at presentation. The most common diagnosis was pilocytic astrocytoma (55%). Chemotherapy was the most common initial treatment modality. Median survival of the group was 6.2 years (range, 0.1–16.9 years). Fifteen (40%) patients died at a median of 6 years from diagnosis (range, 0.8–15 years). Overall survival at 5, 10, and 15 years was 80.7 ± 6.6%, 63.0 ± 10.2%, and 50.9 ± 16.0%, respectively.

Conclusion

This study describes the longest follow‐up of children with metastatic LGG. LGG is underestimated and entails major morbidity and mortality. Prospective studies are needed to learn the true incidence, study the biology, and determine the best approaches to diagnosis, treatment, and follow‐up. Pediatr Blood Cancer 2015; 9999:1–9. © 2015 Wiley Periodicals, Inc.     

Impact of ovarian transposition before pelvic irradiation on ovarian function among long‐term survivors of childhood Hodgkin lymphoma: A report from the St. Jude Lifetime Cohort Study

1 Background

We reviewed the effect of ovarian transposition (OT) on ovarian function among long‐term survivors of childhood Hodgkin lymphoma (HL) treated with pelvic radiotherapy.

2 Procedure

Female participants (age 18+ years) with HL in the St. Jude Lifetime Cohort Study (SJLIFE) were clinically evaluated for premature ovarian insufficiency (POI) 10 or more years after pelvic radiotherapy. Reproductive history including age at menopause and pregnancy/live births was available on all patients.

3 Results

Of 127 eligible females with HL, 90 (80%) participated in SJLIFE, including 49 who underwent OT before pelvic radiotherapy. Median age at STLIFE evaluation was 38 years (range 25–60). In a multiple regression adjusted for age at diagnosis, pelvic radiotherapy doses > 1,500 cGy (hazard ratio [HR] = 25.2, 95% confidence interval [CI] = 3.1–207.3; P = 0.0027) and cumulative cyclophosphamide equivalent doses of alkylating agents > 12,000 mg/m² (HR = 11.2, 95% CI = 3.4–36.8; P < 0.0001) were significantly associated with POI. There was no significant association between OT and occurrence of POI (HR = 0.6, 95% CI = 0.2–1.9; P = 0.41).

4 Conclusions

OT did not appear to modify risk of POI in this historic cohort of long‐term survivors of HL treated with gonadotoxic therapy. Modern fertility preservation modalities, such as mature oocyte cryopreservation, should be offered to at‐risk patients whenever feasible.     

Echocardiographic Detection of Cardiac Dysfunction in Childhood Cancer Survivors: How Long Is Screening Required?

Background

Childhood cancer survivors treated with anthracycline chemotherapy are at an increased risk of long‐term cardiac toxicity, and guidelines recommend that exposed survivors undergo echocardiography every 1–5 years. However, it is unclear whether survivors should undergo echocardiographic screening indefinitely, or if a period of echocardiographic stability indicates that screening is no longer necessary. The objective of this study was to evaluate the outcomes of echocardiographic screening to aid in the refinement of existing guidelines.

Methods

We retrospectively analyzed the results of echocardiographic screening in a cohort of adult survivors of childhood cancer treated with anthracyclines and/or cardiac radiation therapy. Interval regression analysis was performed to identify predictors of single‐episode or sustained abnormal echocardiograms.

Results

The cohort constituted 333 survivors, with median follow‐up time of 15.8 years post‐treatment (range: 5.0–47.9), and median age at treatment of 8 years (range: 1.5–18). Forty‐nine survivors had an abnormal echocardiogram (14.7%), and 29 (8.7%) had reproducible abnormal findings. An ongoing continual increase in the incidence of sustained echocardiographic abnormality was seen among patients treated with >250 mg/m² doxorubicin at age <5 years, reaching 43% by 20 years of therapy. In contrast, no sustained abnormal echocardiographic findings arose after 10 years of therapy in survivors treated with <250 mg/m² at age ≥5 years.

Conclusions

Single‐episode echocardiographic abnormalities are often not reproduced in subsequent evaluations. The duration of echocardiographic screening for childhood cancer survivors should be reassessed for patients who received lower doses of anthracycline after age 5. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.     

Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors

Background

Germline mutations and deletions of SMARCB1/INI1 in chromosome band 22q11.2 predispose patients to rhabdoid tumor and schwannomatosis. Previous estimates suggested that 15–20% of rhabdoid tumors were caused by an underlying germline abnormality of SMARCB1. However, these studies were limited by case selection and an inability to detect intragenic deletions and duplications.

Procedure

One hundred matched tumor and blood samples from patients with rhabdoid tumors of the brain, kidney, or soft tissues were analyzed for mutations and deletions of SMARCB1 by FISH, multiplex ligation‐dependent probe amplification (MLPA), sequence analysis and high resolution Illumina 610K SNP‐based oligonucleotide array studies.

Results

Thirty‐five of 100 patients were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions including regions both proximal and distal to SMARCB1. There were nine cases that demonstrated parent to child transmission of a mutated copy of SMARCB1. In eight of the nine cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma, and two of the eight families presented with multiple affected children in a manner consistent with gonadal mosaicism.

Conclusions

Approximately one‐third of newly diagnosed patients with rhabdoid tumor have an underlying genetic predisposition to tumors due to a germline SMARCB1 alteration. Families may demonstrate incomplete penetrance and gonadal mosaicism, which must be considered when counseling families of patients with rhabdoid tumor. Pediatr Blood Cancer. 2010;56:7–15. © 2010 Wiley‐Liss, Inc.     

Implications of Tumor Location on Subtypes of Medulloblastoma

Background

Medulloblastoma (MB) comprises of four molecular subtypes, Sonic hedgehog (SHH), Wingless (WNT), Groups 3 and 4. WNT‐subtype MBs were found to arise from midline of the brainstem occupying the fourth ventricle while SHH‐subtype occupied the cerebellar hemisphere in a small subset of patients.

Procedure

We tested this hypothesis in a large cohort of pediatric MBs comprising of all four molecular subtypes.

Results

We validated in the first comprehensive analysis of tumor location of 60 human MBs representative of the four molecular subtypes, that hemispheric tumors are significantly associated with SHH‐subtype MBs while midline tumors with WNT‐subtype, Group 3 and 4 MBs (P < 0.001). Nearly half of SHH‐subtype MBs were midline.

Conclusions

Tumor location should not be generalized to MB subtypes. SHH‐subtype MBs are not exclusively hemispheric and hemispheric MBs are not always SHH‐activated. It is imperative to identify subtypes in conjunction with tumor location when exploring currently available targeted therapy. Pediatr Blood Cancer 2013;60:1408–1410. © 2013 Wiley Periodicals, Inc.     

Mismatch repair deficiency is an uncommon mechanism of alkylator resistance in pediatric malignant gliomas: A report from the children's oncology group

Background

Alkylating agents are commonly used in the treatment of childhood malignant gliomas. Overexpression of O⁶‐methylguanine‐DNA methyltransferase (MGMT) constitutes an important mechanism for resistance to such agents, and MGMT status has been associated with outcome in several recent trials. Deficiency in mismatch repair (MMR) function has been implicated in preclinical studies as an additional potential mechanism of resistance to methylating agents, such as temozolomide, independent of tumor MGMT status. However, the frequency of this abnormality as a clinical resistance mechanism in childhood malignant gliomas has not been well characterized.

Methods

To address this issue, we examined the frequency of microsatellite instability (MSI), a marker of defective MMR, in a series of 68 tumors, derived from newly diagnosed patients treated on the Children's Cancer Group 945 study, and the Children's Oncology Group ACNS0126 and 0423 studies. MSI was assessed using a panel of six microsatellite markers, including BAT‐25, BAT‐26, CAT‐25, D2S123, D5S346, and D17S250. MGMT immunoreactivity was assessed in parallel to allow comparison of the relative incidence of MGMT overexpression and MSI.

Results

Only three tumors had high‐level MSI involving three or more markers; the remainder had no MSI at any of the loci examined. These children did not have unusual features in terms of their outcome. In contrast to the infrequency of MSI, 25 tumors (37%) exhibited MGMT overexpression as assessed by immunohistochemistry. None of the tumors with MSI exhibited overexpression of MGMT.

Conclusion

MMR deficiency is an infrequent contributor to initial alkylator resistance in children with malignant gliomas. Pediatr Blood Cancer. 2010;55:1066–1071. © 2010 Wiley‐Liss, Inc.     

Nephrolithiasis in pediatric hematopoietic cell transplantation with up to 40 years of follow‐up

Background

Kidney stones have been reported to occur after childhood cancer, but little is known about kidney stones in children following hematopoietic cell transplantation (HCT). The objective of this retrospective study was to determine risk factors for the development of kidney stones and to describe the prevalence among survivors.

Procedure

The study included 1,343 childhood HCT patients. Mean follow‐up was 15.8 (1.0–40.0) years. Patients were treated with total body irradiation (TBI) (n = 948) or non‐TBI regimens. Methotrexate (MTX) for acute graft‐versus‐host disease (GVHD) prophylaxis was given as long‐course (n = 360), short‐course (n = 626), or none (n = 357). Prednisone for chronic GVHD therapy was received by 525 patients. Multivariate Cox regression models were used to estimate the hazard ratio (HR) of risk factors associated with kidney stones.

Results

Kidney stones developed in 51 patients, a median of 9.9 (0.2–29.4) years after first HCT, with a 30‐year cumulative incidence of 7.4%. Risk factors associated with kidney stones were TBI (HR = 2.2; P = 0.03), age at HCT (12–18 vs. <6 years, HR = 2.7; P = 0.01), MTX (long vs. none, HR = 3.6; P = 0.02), and prednisone (HR = 2.2; P = 0.008). Among 868 survivors, the prevalence of a history of kidney stones was 4.7%.

Conclusions

Survivors of childhood HCT have an increased risk of developing kidney stones. Pediatr Blood Cancer 2014;61:417–423. © 2013 Wiley Periodicals, Inc.     

Gonadal function and parenthood 20 years after treatment for childhood lymphoma: a cross-sectional study

Background

Gonadal function decades after treatment for childhood lymphoma (CL) is not well described. This cross‐sectional study had two aims: (1) describe long‐term gonadal function and fertility in childhood lymphoma survivors (CLSs), and (2) explore anti‐Mullerian hormone (AMH) as a measure of ovarian function in CLSs.

Procedure

Seventy‐four male and 62 female CLSs participated in a survey consisting of a questionnaire, clinical examination, and blood/semen analysis. Prior treatment was categorized according to gonadotoxicity. Hypogonadism was determined by levels of gonadal hormones based on luteinizing hormone, follicle‐stimulating hormone, testosterone (males), AMH (females <40 years), and menstrual status. Fertility was explored according to pregnancies achieved, semen analysis, and AMH.

Results

Hypogonadism was observed in 7 of 66 males (11%). Seven of 64 males (11%) were categorized as infertile. Nine of 45 females <40 years (20%) were at risk to develop premature ovarian failure (POF). Twenty of 45 females (44%) showed low‐AMH levels indicating decreased fertility. Four “critically low” females reported pregnancies within the preceding 2 years. Sixty‐four percent of the males and 93% of the females attempting parenthood had been successful (P = 0.01). Hypogonadism and low‐AMH were related to treatment burden.

Conclusion

Twenty years after treatment of CL, female CLSs' attempts of pregnancy initiation are mostly successful, while males seem at higher risk of infertility. Hypogonadism is a problem in 10% of the male CLSs. Based on AMH levels, POF is a risk in 20% of the female CLSs. The clinical significance of AMH reflecting true probability of fertility needs further research in cancer survivors. Pediatr Blood Cancer 2012;59:271–277. © 2011 Wiley Periodicals, Inc.     

A retrospective case–control study of gastrostomy use in children undergoing hematopoietic cell transplantation

Background

Maintaining a good nutritional status during the hematopoietic cell transplantation (HCT) procedure is challenging in the pediatric population.

Methods

In a multicentric retrospective study, we compared the outcome of nutritional status and HCT-related parameters in 227 pediatric patients during and after HCT between 2005 and 2015. 112 patients received a gastrostomy before the start of HCT (GS group), and 115 did not receive a gastrostomy (NGS). Data collection was performed at HCT, 3, 6, and 12 months post-HCT.

Results

At time point of HCT the Standard Deviation Score (SDS) of weight was 0.17 in the NGS group, and 0.71 in the GS group (p = .01) Patients in the NGS group lost more weight during the first 3 months after HCT than patients in the GS group. At 12 months, patients in the NGS remained at a lower weight, while patients in the GS group slightly increased their weight. There were no differences between the groups in the incidence of acute graft-versus-host-disease (GvHD), overall survival, and non-relapse mortality. However, the number of febrile episodes requiring intravenous treatment with antibiotics, was higher in the GS group as compared to the NGS group, during the first 3 months post-HCT (p < .001).

Conclusions

Our results indicate that gastrostomy can be utilized in children undergoing HCT without any negative effects on mortality. Therefore, the use of a gastrostomy appears to be a safe option to maintain a good nutritional status during the HCT procedure.     

Long-term complications in totally implantable venous access devices: randomized study comparing subclavian and internal jugular vein puncture

Background

This prospective randomized study evaluated complications related to long‐term totally implantable catheters in oncologic children and adolescents by comparing venopunction performed either in the jugular or subclavian vein.

Methods

A total of 83 catheters were implanted from January 2004 to April 2006 and followed‐up until March 2008. Patients were randomly allocated to the subclavian or jugular vein group. The endpoint was complications that led to catheter revision or catheter removal.

Results

Six patients were excluded, 43 had the catheter implanted in the subclavian and 34 in the jugular vein. Subclavian catheters were used for up to 12.6 months, while jugular catheters were kept in place for up to 14.8 months (P = 0.38). No statistical differences were found between the groups concerning age, sex, leukocyte count, platelet count, type of admission (in or outpatient), or previous chemotherapy regimens. When analyzed individually, long‐term complications did not present statistically significant differences either. Infection occurred in 20 and 11% (P = 0.44), while catheter embolism took place in 23 and 8% (P = 0.11) of patients with subclavian and jugular catheters, respectively. A statistical difference was seen in the total number of complications, which occurred in 48 and 23% (P = 0.02) of patients in the subclavian and in the jugular groups, respectively.

Conclusions

Catheters implanted by puncture in the subclavian vein were more prone to late complications than those implanted in the jugular vein. Pediatr Blood Cancer 2012; 58: 274–277. © 2011 Wiley Periodicals, Inc.     

Echocardiographic surveillance for asymptomatic late-onset anthracycline cardiomyopathy in childhood cancer survivors

Background

The optimal frequency of echocardiographic surveillance in asymptomatic childhood cancer survivors exposed to anthracyclines has not been established. We evaluated the effectiveness of performing surveillance echocardiograms according to the Children's Oncology Group's (COG) Long‐Term Follow‐Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers in survivors ≥1 year from concluding therapy.

Methods

We reviewed all children treated at our institution with anthracycline chemotherapy from 1995 to 2003. We assessed the frequency of abnormal echocardiograms according to risk groups defined in the COG guidelines, and evaluated the risk factors for an abnormal echocardiogram using Cox proportional hazards modeling.

Results

At least one echocardiogram was completed by 469/603 (77.8%) eligible survivors. Mean diagnosis age was 7.7 (SD = 4.6) years. Mean cumulative doxorubicin‐equivalent dose was 205 mg/m² (SD = 115). Survivors completed 1,013 echocardiograms (median = 2, range = 1–10) beyond 1 year after concluding therapy. Seventy‐nine (16.8%) survivors had an abnormal echocardiogram at a median of 2.9 years (range 0.01–9.8) from 1 year after concluding therapy. Anthracycline dose >300 mg/m² (hazard ratio [HR] 3.00; 95% CI 1.51–5.98), age 1–4 years at treatment (HR 1.89; 95% CI 1.08–3.31) and radiation to a field involving the heart (HR 1.73; 95% CI 1.08–2.76) predicted an increased risk of an abnormal echocardiogram; however, even survivors in the lower COG risk groups demonstrated abnormalities.

Conclusion

Periodic echocardiographic surveillance in childhood cancer survivors can yield abnormalities that require further evaluation. Abnormalities may become evident as early as 1 year after the conclusion of therapy and can impact even those survivors considered to be at low risk. Pediatr Blood Cancer 2011; 57: 467–472. © 2011 Wiley‐Liss, Inc.     

Prevalence and predictors of anthracycline cardiotoxicity in children treated for acute myeloid leukaemia: retrospective cohort study in a single centre in the United Kingdom

Background

Anthracycline cardiomyopathy is of concern in children treated for acute myeloid leukaemia (AML), but there are few data on the incidence and natural history of cardiotoxicity after AML treatment in the United Kingdom, where regimens have included high anthracycline exposure.

Procedure

Prevalence and predictors of cardiotoxicity were retrospectively reviewed in 124 children treated on the MRC AML 10 and AML 12 trials in a single, large centre from November 1987 to September 2004. Subclinical cardiotoxicity was defined as a shortening fraction of less than 28% and clinical cardiomyopathy as evidence of heart failure, and both were classified as late cardiotoxicity 1 year after completing first line therapy.

Results

Cumulative survival was 61% at 10 years. The prevalence of early and late cardiotoxicity was 13.7% (95%‐CI: 8.2–22.0%) and 17.4% (95%‐CI: 10.9–26.8%), respectively. Early cardiotoxicity was a strong predictor (OR = 9.18; 95%‐CI: 2.10–40.11; P < 0.005) and children who received salvage therapy following relapse showed a trend towards increased late cardiotoxicity (OR = 3.53; 95%‐CI: 0.86–14.48; P < 0.08). Subclinical cardiotoxicity resolved spontaneously in all but one case, but clinical cardiomyopathy always required continuing therapy. Two children died of cardiomyopathy and six remained on medical therapy.

Conclusions

Anthracycline cardiotoxicity remains a major concern for survivors of childhood AML and correlates with early cardiotoxicity and treatment intensity. Long‐term follow‐up is required to fully determine the outcome for children with subclinical cardiotoxicity. Pediatr Blood Cancer 2011;56:625–630. © 2011 Wiley‐Liss, Inc.     

Mortality in children with low‐grade glioma or glioneuronal tumors: A single‐institution study

1 Background

While pediatric low‐grade glioma/glioneuronal tumors (LGG/LGGNTs) are considered slow‐growing, indolent tumors with excellent long‐term prognosis, mortality due to the disease is not unknown. Few studies have addressed the cause of death in this population.

2 Methods

Retrospective review of clinicopathologic and radiologic data for children 21 years or younger with LGG/LGGNT who died at St. Jude Children's Research Hospital between April 1985 and June 2015. Our primary objective was to determine the causes and timing of mortality in affected children.

3 Results

For the 87 eligible patients, median age at diagnosis was 7.7 years (range, 0.21–21 years), median age at death was 14.26 years (range, 0.58–32 years), and median time to death from diagnosis was 4.02 years (range, 0.21–24 years). Midbrain/thalamus was the most common tumor location (n = 34), followed by suprasellar/hypothalamic (n = 18) and cerebrocortical (n = 13). Astrocytoma not otherwise specified (n = 24), pilocytic astrocytoma (n = 23), and fibrillary astrocytoma (n = 11) were the predominant histologic diagnoses. Causes of death included progressive primary disease (PD) (n = 43), progression of PD with histological features of a high‐grade glioma at progression or at autopsy (PD‐HGG) (n = 15), second cancer (n = 3), suicide (n = 4), and vehicular accident (n = 3). Among the 15 patients with PD‐HGG, 12 received radiation therapy before histologic confirmation of progression.

4 Conclusions

PD and PD‐HGG contributed to 66% of the mortality in our patient cohort. Early psychological intervention should be included as part of the multidisciplinary management approach of children with LGG/LGGNT to reduce the risk of suicide in vulnerable subjects.     

Long-term results in childhood rhabdomyosarcoma: a report from the Italian Cooperative Study RMS 79

Background

The results obtained by protocols for children with rhabdomyosarcoma (RMS) have improved in recent decades. Survival curves usually reach a plateau 3 years after the diagnosis, suggesting that long‐term survival can be expected, but late events are known to occur. We analyzed the long‐term results of the RMS 79 protocol to investigate the type and impact of such events.

Procedure

From 1979 to 1987, 163 children with RMS diagnosed at 21 Italian institutions were registered. Each institution was contacted every year to record patients' status after the end of treatment. When patients were lost to follow‐up, their status was checked by inquiring at the Registry Offices of the towns of residence and the cause of death or occurrence of second cancers was investigated by contacting the patients or their family by phone.

Results

Overall, 16 patients had late events, that is, 7 tumor recurrences, 6 second tumors, and 3 deaths due to treatment‐related complications. The overall survival rates dropped from 62.6 at 3 years to 52.8 at 20 years. By multivariate analysis, the characteristics influencing long‐term survival were histology, tumor site and size, and IRS group. Factors predictive of any kind of late event were tumor site and IRS group.

Conclusions

Major late events can significantly affect the long‐term survival of children with RMS. Modern protocols should provide for a much longer follow‐up than is usually considered to confirm the results achieved and enable possible correlations between primary treatment and late events to be investigated. Pediatr Blood Cancer 2012; 58: 872–876. © 2011 Wiley Periodicals, Inc.