Treatment In Childhood Cancer Survivors Research Articles

Physical late effects of treatment among survivors of childhood cancer in low- and middle-income countries: a systematic review.

Physical late effects of treatment are well-documented among childhood cancer survivors in high-income countries, but whether prevalence and risk factors are comparable in low- and middle-income countries (LMICs) is unclear. We conducted a systematic review to assess physical late effect outcomes among childhood cancer survivors in LMICs. Five health sciences databases were searched from inception to November 2022 in all languages. We included observational studies conducted in LMICs that evaluated physical late effects of treatment in childhood cancer survivors. Mean or median cohort follow-up must have been ≥ 5 years from original cancer diagnosis. Sixteen full articles and five conference abstracts were included. Studies were conducted in lower-middle (n = 12, 57%) or upper-middle income (n = 9, 43%) countries; nearly half (n = 9, 43%) were conducted in India. Five cohorts (24%) were comprised entirely of 5-year survivors. Subsequent malignant neoplasms were reported in 0-11% of survivors (n = 10 studies). Hypothyroidism and metabolic syndrome prevalence ranged from 2-49% (n = 4 studies) and 4-17% (n = 5 studies), respectively. Gonadal dysfunction ranged from 3-47% (n = 4 studies). Cardiac dysfunction ranged from 1-16% (n = 3 studies). Late effects of the musculoskeletal and urinary systems were least investigated. Substantial knowledge gaps exist in LMIC childhood cancer survivorship. No low-income country data were found. In middle-income countries, late effects were defined and assessed variably and limited by selection bias and small sample sizes. Survivors in LMICs can experience physical late effects of treatment, though additionally systematically collected data from survivor cohorts are needed to fill knowledge gaps.

Abstract 4514: Variations of blood DNA methylation associated with cancer treatment exposures among childhood cancer survivors of African ancestry

Abstract We previously showed that cancer treatment associated DNA methylation (DNAm) signatures were present decades following the cancer diagnosis in childhood cancer survivors (CCS) of European ancestry (EA) and that treatment associated DNAm sites mediated the causal pathway from specific treatment exposures to increased risk of chronic health conditions (CHCs). This new analysis further evaluated and compared the treatment and DNAm associations in CCS of African ancestry (AA) from the St. Jude Lifetime Cohort Study. Cancer treatments were abstracted from medical records. DNAm was measured using MethylationEPIC BeadChip with blood-derived DNA. Among 370 AA CCS (53.2% female, median age at blood draw=31.2 [range=18.4-65.1] years), treatments included alkylating agents (54.6%), anthracyclines (48.6%), epipodophyllotoxins (29.2%), corticosteroids (33.0%), and vincristine (61.6%), and radiation therapy (RT) to brain (26.5%), chest (27.6%), abdomen (22.7%), and pelvis (21.6%). Epigenome-wide association study (EWAS) for each treatment, using multivariable linear regression adjusting for sex, age at blood draw, leukocyte cell subtype proportions, genotype principal components and DNAm principal components, showed little inflation with genomic control (GC) factor between 1.1 (brain-RT) and 1.2 (chest-RT). A total of 93 5′-cytosine-phosphate-guanine-3′ (CpG) was associated with one or more cancer treatments (GC-adjusted P<9 × 10−8), including epipodophyllotoxins (n=46), alkylating agents (n=38), corticosteroids (n=3), anthracyclines (n=3), abdominal-RT (n=3), chest-RT (n=2), and pelvic-RT (n=1). A total of 60 differentially methylated regions (DMRs) was identified using DMRcate R package, including alkylating agents (n=28), epipodophyllotoxins (n=22), corticosteroids (n=3), abdominal-RT (n=4), chest-RT (n=2), and anthracyclines (n=1). A total of 39 CpGs from EWAS were nested within 21 DMRs. 92.1% (650/706) chemo-associated CpGs in EA were replicated in AA CCS, and 98.9% (86/87) chemo-associated CpGs in AA were replicated in EA CCS. In contrast, 66.7% (4/6) RT-associated CpGs in AA were replicated in EA CCS, and 71.7% (638/890) RT-associated CpGs in EA were replicated in AA CCS. Moreover, the four CpGs that partially mediated the effect of abdominal-RT on hypercholesterolemia in EA were not associated with abdominal-RT in AA CCS, further suggesting substantial difference in RT-associated CpGs as compared to chemo-associated CpGs between AA and EA CCS. Future studies by including a larger sample size of AA CCS are warranted to assess the difference in treatment-associated DNAm alterations and subsequent disparity in risk of treatment-related CHCs between AA and EA CCS. The DNAm sites can be used as predictors for risk management (treatment decision-making) and potential mechanistic targets for intervention for those at the greatest risk of CHCs. Citation Format: Qian Dong, Sarmistha Das, Cheng Chen, John Easton, Heather L. Mulder, Emily Walker, Geoffrey Neale, Deo Kumar Srivastava, I-Chan Huang, Jinghui Zhang, Melissa M. Hudson, Leslie L. Robison, Kirsten K. Ness, Nan Song, Zhaoming Wang. Variations of blood DNA methylation associated with cancer treatment exposures among childhood cancer survivors of African ancestry. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4514.

Dental caries and dental developmental defects as adverse effects of antineoplastic treatment in childhood cancer survivors.

To evaluate the prevalence of dental caries and dental developmental defects (DDD) in childhood cancer survivors (CCS) and identify disease and treatment-related risk factors. CCS aged up to 21years, diagnosed with a malignancy before the age of 10years and in remission for at least one year were included. Data were collected from patients' medical records and through a clinical examination where presence of dental caries and prevalence of DDD were recorded. Fisher's exact test was used to assess possible correlations and multivariate regression analysis to determine risk factors for defect development. Seventy CCS with a mean chronological age of 11.2years at the time of examination, mean age at cancer diagnosis of 4.17years, and a mean post-treatment follow-up time of 5.48years were included. Mean DMFT/dmft was 1.31, with 29% of survivors presenting with at least one carious lesion. Younger patients on the day of examination and patients treated with higher radiation dose, showed significantly higher prevalence of dental caries. The prevalence of DDD was 59%, with demarcated opacities being the defect most commonly observed (40%). Age at dental examination, diagnosis, age at diagnosis, and time that have elapsed since the end of treatment were the factors significantly affecting its prevalence. Regression analysis revealed that age at examination was the only factor significantly associated with the presence of coronal defects. A great number of CCS presented with at least one carious lesion or a DDD, with the prevalence being significantly associated with various disease-specific characteristics, but age at dental examination the only significant predictor.

Evaluation of health-related quality of life in childhood cancer survivors

BackgroundConsidering the high survival rates of childhood cancers and their stable incidence, concepts such as quality of life (QOL) and health-related quality of life (HRQOL) are impactful issues that have consistently retained their importance worldwide. ObjectiveThis study aimed to evaluate HRQOL at least 5 years after treatment in childhood cancer survivors (CCSs) with the hypothesis that their QOL could be adversely affected later in their lives. Additionally, we sought to assess the parents of pediatric CCSs with respect to HRQOL. Patients and MethodsWe evaluated CCSs aged 8–18 years and compared the results with healthy controls (matched for age and sex). The parents of the pediatric CCSs and control groups were also analyzed. A total of 174 cases (patients and controls) and 168 parents (of patients and controls) were included in the study. HRQOL was evaluated by applying the Pediatric Quality of Life Inventory (PedsQL). ResultsThe mean HRQOL scores of CCSs were significantly lower than those of the controls (p= 0.04). No differences were found between the parents of these groups. The physical and social functionality scores of CCSs were significantly lower when compared to healthy controls (p = 0.02 and p<0.01, respectively). In addition, according to cancer type, the HRQOL scores of those with solid tumors were found to be significantly lower than those with hematological cancers (p=0.02).(p = 0.02) ConclusionThis study shows that HRQOL is lower in CCSs compared to healthy controls. The most important differences in HRQOL among CCSs were found in the physical and social subdimensions compared to the controls. In this regard, it appears to be vital to provide mental support to CCSs after cancer treatment. These findings also indicate the need for health-focused social policies that can increase HRQOL in CCSs.

Electrocardiographic abnormalities in childhood cancer survivors treated with cardiotoxic therapy: a systematic review.

The purpose of this study is to assess the available literature on the prevalence and risk factors of electrocardiographic (ECG) abnormalities after cardiotoxic treatment in childhood cancer survivors (CCS). A literature search was performed within MEDLINE, EMBASE, and CENTRAL (1966-11/2020) and reference lists of relevant studies. Studies were eligible for inclusion if they reported ECG abnormalities ≥2 years after cancer diagnosis in ≥50 CCS treated with anthracyclines, RT involving the heart region and/or mitoxantrone. Information about population, treatment, outcome, and risk factors were extracted and risk of bias was assessed. Of 934 identified publications, 10 studies were included. Outcome definitions, treatment regimens, follow-up period, and risk of bias varied. These ECG abnormalities and prevalences were reported: major (5%-23%) and minor (12%) abnormalities according to the Minnesota Code, rhythm abnormalities (0%-12%), conduction abnormalities (0.3%-7.1%), depolarization abnormalities (0%), and repolarization abnormalities (0%-65%). The reported risk factors of ECG abnormalities (two studies) are male sex, anthracyclines, RT involving the heart region, and hypertension, although results were not univocal between studies and abnormalities. Multiple ECG abnormalities have been described in CCS ≥2 years from diagnosis, some of which can have important implications. Future research is needed to evaluate the exact long-term incidence and risk factors, and to investigate their clinical relevance and relation with cardiac dysfunction or future cardiac events. This could improve cardiac surveillance for CCS.

Late side effects of cancer treatment in childhood cancer survivors.

Childhood cancers are usually treated with chemotherapy and radiation. Therefore, understanding the late side effects of such treatments is important to improve the quality of life in childhood cancer survivors. The present study aimed to investigate the late complications of treatments in childhood cancer survivors. This study is a retrospective descriptive study. A total number of 93 cases were enrolled in this study. These cases had a history of childhood cancer documented in their medical records at the Shafa Hospital, Ahvaz, Iran. The age range was 5.9-21.3 years and included 62 males and 31 female patients. Many of the patients at this hospital with childhood cancer had experienced chemotherapy side effects as well as late effects of cancer therapy. Hypothyroidism is a late complication of therapy in thoracic cancers and head/neck tumors with relative frequencies of 23.1% and 12.5%, respectively. Scoliosis was observed in the patients undergoing the ABVD + COPP and 8/1 regimens with relative frequencies of 4% and 50%, respectively. Lower growth percentiles were also late side effects of cancer therapy. The highest relative frequency of growth retardation was observed in the <5 age group (46.7%). Restrictive lung changes had an overall relative frequency of 6.5% in male patients with all types of tumors. Sensorineural hearing loss was observed in patients with leukemia and Hodgkin lymphoma with relative frequencies of 8.7% and 24.0, respectively. The occurrence of most side effects could be decreased through early diagnosis, dose adjustment of some drugs, and preventative measures.

Late effects of high-dose methotrexate treatment in childhood cancer survivors\u2014a systematic review

BackgroundHigh-dose methotrexate (HD-MTX) is used in the treatment of different childhood cancers, including leukemia, the most common cancer type and is commonly defined as an intravenous dose of at least 1 g/m2 body surface area per application. A systematic review on late effects on different organs due to HD-MTX is lacking.MethodWe conducted a systematic literature search in PubMed, including studies published in English or German between 1985 and 2020. The population of each study had to consist of at least 75% childhood cancer survivors (CCSs) who had completed the cancer treatment at least twelve months before late effects were assessed and who had received HD-MTX. The literature search was not restricted to specific cancer diagnosis or organ systems at risk for late effects. We excluded case reports, case series, commentaries, editorial letters, poster abstracts, narrative reviews and studies only reporting prevalence of late effects. We followed PRISMA guidelines, assessed the quality of the eligible studies according to GRADE criteria and registered the protocol on PROSPERO (ID: CRD42020212262).ResultsWe included 15 out of 1731 identified studies. Most studies included CCSs diagnosed with acute lymphoblastic leukemia (n = 12). The included studies investigated late effects of HD-MTX on central nervous system (n = 10), renal (n = 2) and bone health (n = 3). Nine studies showed adverse outcomes in neuropsychological testing in exposed compared to non-exposed CCSs, healthy controls or reference values. No study revealed lower bone density or worse renal function in exposed CCSs. As a limitation, the overall quality of the studies per organ system was low to very low, mainly due to selection bias, missing adjustment for important confounders and low precision.ConclusionsCCSs treated with HD-MTX might benefit from neuropsychological testing, to intervene early in case of abnormal results. Methodological shortcomings and heterogeneity of the tests used made it impossible to determine the most appropriate test. Based on the few studies on renal function and bone health, regular screening for dysfunction seems not to be justified. Only screening for neurocognitive late effects is warranted in CCSs treated with HD-MTX.

Growth Hormone Deficiency and Treatment in Childhood Cancer Survivors.

Growth hormone (GH) deficiency is a common pituitary hormone deficiency in childhood cancer survivors (CCS). The identification, diagnosis, and treatment of those individuals at risk are important in order to minimize associated morbidities that can be ameliorated by treatment with recombinant human GH therapy. However, GH and insulin-like growth factor-I have been implicated in tumorigenesis, so there has been concern over the use of GH therapy in patients with a history of malignancy. Reassuringly, GH therapy has not been shown to increase risk of tumor recurrence. These patients have an increased risk for development of meningiomas, but this may be related to their history of cranial irradiation rather than to GH therapy. In this review, we detail the CCS who are at risk for GHD and the existing evidence on the safety profile of GH therapy in this patient population.

Risk of radiation-induced second malignant neoplasms from photon and proton radiotherapy in paediatric abdominal neuroblastoma.

Background and PurposeState-of-the-art radiotherapy modalities have the potential of reducing late effects of treatment in childhood cancer survivors. Our aim was to investigate the carcinogenic risk associated with 3D conformal (photon) radiation (3D-CRT), intensity modulated arc therapy (IMAT) and pencil beam scanning proton therapy (PBS-PT) in the treatment of paediatric abdominal neuroblastoma.Materials and MethodsThe risk of radiation-induced second malignant neoplasm (SMN) was estimated using the concept of organ equivalent dose (OED) for eleven organs (lungs, rectum, colon, stomach, small intestine, liver, bladder, skin, central nervous system (CNS), bone, and soft tissues). The risk ratio (RR) between radiotherapy modalities and lifetime absolute risks (LAR) were reported for twenty abdominal neuroblastoma patients (median, 4y; range, 1-9y) historically treated with 3D-CRT that were also retrospectively replanned for IMAT and PBS-PT.ResultsThe risk of SMN due to primary radiation was reduced in PBS-PT against 3D-CRT and IMAT for most patients and organs. The RR across all organs ranged from 0.38 ± 0.22 (bladder) to 0.98 ± 0.04 (CNS) between PBS-PT and IMAT, and 0.12 ± 0.06 (rectum and bladder) to 1.06 ± 0.43 (bone) between PBS-PT and 3D-CRT. The LAR for most organs was within 0.01–1% (except the colon) with a cumulative risk of 21 ± 13%, 35 ± 14% and 35 ± 16% for PBS-PT, IMAT and 3D-CRT, respectively.ConclusionsPBS-PT was associated with the lowest risk of radiation-induced SMN compared to IMAT and 3D-CRT in abdominal neuroblastoma treatment. Other clinical endpoints and plan robustness should also be considered for optimal plan selection.

Metabolic syndrome induced by anticancer treatment in childhood cancer survivors.

The number of childhood cancer survivors is increasing as survival rates improve. However, complications after treatment have not received much attention, particularly metabolic syndrome. Metabolic syndrome comprises central obesity, dyslipidemia, hypertension, and insulin resistance, and cancer survivors have higher risks of cardiovascular events compared with the general population. The mechanism by which cancer treatment induces metabolic syndrome is unclear. However, its pathophysiology can be categorized based on the cancer treatment type administered. Brain surgery or radiotherapy may induce metabolic syndrome by damaging the hypothalamic-pituitary axis, which may induce pituitary hormone deficiencies. Local therapy administered to particular endocrine organs directly damages the organs and causes hormone deficiencies, which induce obesity and dyslipidemia leading to metabolic syndrome. Chemotherapeutic agents interfere with cell generation and growth, damage the vascular endothelial cells, and increase the cardiovascular risk. Moreover, chemotherapeutic agents induce oxidative stress, which also induces metabolic syndrome. Physical inactivity caused by cancer treatment or the cancer itself, dietary restrictions, and the frequent use of antibiotics may also be risk factors for metabolic syndrome. Since childhood cancer survivors with metabolic syndrome have higher risks of cardiovascular events at an earlier age, early interventions should be considered. The optimal timing of interventions and drug use has not been established, but lifestyle modifications and exercise interventions that begin during cancer treatment might be beneficial and tailored education and interventions that account for individual patients' circumstances are needed. This review evaluates the recent literature that describes metabolic syndrome in cancer survivors, with a focus on its pathophysiology.

Growth hormone treatment in childhood cancer survivors

Growth hormone (GH) deficiency is one of the most frequent endocrine problems occurring in cancer survivors, particularly when there is a previous history of central nervous system (CNS) tumour and submission to radiotherapy (RT). We retrospectively assessed pediatric cancer survivors with GH deficiency, submitted to GH treatment from 1988 to 2010 in a tertiary level hospital. We analised the following data: sex, age, oncologic diagnosis, oncologic treatment, auxology, Tanner puberty stage, final height, target height and other associated endocrine problems. We determined the height z-score difference between the beginning and the end of GH treatment (for patients who ended treatment), and between the beginning of GH treatment and the last observation (for patients who are currently on treatment), which was defined as the dependent variable. SPSS® version 17.0 was used for statistical analysis. A sample of 18 patients was obtained, 12 male, with a median age of cancer diagnosis of six years old. The diagnostics were CNS tumors (n=15) and hematologic neoplasia (n=3). Cancer treatment modalities were craniospinal RT (n=9), cranial RT (n=4), chemotherapy (n=14) and CNS surgery (n=15). The median of time between cancer treatment and beginning of GH treatment was 4 years and 8 months. Height z-score difference was positive in 12 patients. Statistical significant differences between medians and centiles of height z-score difference occurred in patients submitted to craniospinal RT (-0.08), cranial RT (0.59) and no RT (1.56) (p=0.003, IC 95%). The biggest differences between final height and target height (-10 and -11.5 cm) occurred in two patients submitted to craniospinal RT, with associated precocious puberty. Our results are consistent with previous studies, which point to a lesser efficacy of GH treatment when there is a past history of RT, namely craniospinal RT, and in association with precocious puberty.

Management of Asymptomatic Anthracycline-Induced Cardiac Damage After Treatment for Childhood Cancer

Asymptomatic anthracycline-induced cardiac damage (A-CD) is a serious problem among young childhood cancer survivors. The aim of this survey was to assess the current treatment policy in these patients in the Netherlands. A questionnaire was sent to all 136 departments of adult or pediatric cardiology in the Netherlands. It was returned by 61% of the departments. Sixty-six percent of the respondents started medical treatment (ie, an ACE inhibitor and/or a beta-blocker) in childhood cancer survivors with asymptomatic A-CD. Fifty-eight percent of the respondents indicated that their treatment decision was based on published findings in the literature, but none of them referred to studies evaluating the treatment of asymptomatic A-CD. A majority of adult and pediatric cardiologists started medical treatment in childhood cancer survivors with asymptomatic A-CD without knowledge of the benefits and risks of treatment in this patient group. Before ACE inhibitors and/or beta-blockers can be recommended as routine practice in childhood cancer survivors with asymptomatic A-CD, randomized controlled trials should be performed. Until then, the authors recommend centralizing the treatment of childhood cancer survivors with asymptomatic A-CD in a specialized center to cluster the available knowledge and experience.

Psychological long‐term coping with experience of disease and treatment in childhood cancer survivors

Childhood cancer, although cured, may have long-term psychological consequences for the adult survivor. The outcome of patients' coping with the illness and treatment experience was assessed in relation to a theoretical model describing optimal long-term coping with a potential psychic trauma of this nature. Thirty young adult childhood cancer survivors were studied. The average age at diagnosis was 8 years, and at evaluation 22 years. The average time since diagnosis was 13 years. The evaluations of coping were carried out independently by two psychologists, who rated material from semistructured in-depth interviews. By statistical cluster analysis three clusters were produced that could be interpreted as exhibiting "good," "intermediate" and "poor" coping, containing 40, 33, and 27%, respectively, of the total group. Overall cluster differences were statistically significant. Profile analysis revealed statistical stability and internal homogeneity in the good coping cluster and the poor coping cluster.