The evolution of nutritional care in children and young people with acute lymphoblastic leukaemia: a narrative review.

BACKGROUND: Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy in the world. Advances in treatment protocols have resulted in survival rates of >80% in most high-income countries (HIC); however, children and young people (CYP) with ALL continue to face significant nutrition-related challenges during treatment. METHODS: This narrative review outlines the changing landscape of treatment and survivorship for CYP with ALL and the advances in nutrition knowledge that call for changes to clinical nutrition practice. RESULTS: The incidence of ALL has remained stable in HIC; however, there have been significant advances in survival over the past 30 years. Overweight and obesity are increasingly prevalent in CYP with ALL at diagnosis, during treatment and in survivorship. Coupled with poor diet quality, high-energy and saturated fat intakes, altered eating behaviours and inactivity, this necessitates the need for a shift in nutrition intervention. Undernutrition remains a concern for CYP with high-risk treatment protocols where oral or enteral nutrition support remains a cornerstone of maintaining nutrition status. CONCLUSIONS: With improved treatment protocols and high survival rates, a shift to focusing on diet quality, prevention of excessive weight gain and obesity during treatment and survivorship is necessary.

Adjuvant chemotherapy does not improve outcome in children with ovarian immature teratoma: A comparative analysis of clinical trial data from the Malignant Germ Cell International Consortium.

BACKGROUND/OBJECTIVES: Surgery is the mainstay of therapy for children with ovarian immature teratoma (IT), whereas adults receive adjuvant chemotherapy, except those with stage-I, grade-1 disease. In Brazil, children with metastatic ovarian IT received postoperative chemotherapy. This practice variation allowed evaluation of the value of chemotherapy, by comparison of Brazilian patients with those in the United States and United Kingdom. DESIGN/METHODS: From the Malignant Germ Cell International Consortium data commons, data on ovarian IT patients from two recently added Brazilian trials (TCG-99/TCG-2008) were compared with data from US/UK (INT-0106/GC-2) trials. Primary outcome measure was event-free (EFS) and overall survival (OS). RESULTS: Forty-two Brazilian patients were included (stage I: 27, stage II: 4, stage III: 8, stage IV: 3). Twenty-nine patients had surgery alone, whereas 13 patients received postoperative chemotherapy. The EFS and OS for entire cohort was 0.80 (95% CI: 0.64-0.89) and 0.97 (0.84-0.99). There was no difference in relapse risk based on stage, grade, or receipt of chemotherapy. Comparing the Brazilian cohort with 98 patients in US/UK cohort (stage I: 59, stage II: 12, stage III: 27), there was no difference in EFS and OS across all stages, despite 87% of stage II-IV Brazilian patients receiving postoperative chemotherapy compared with only 13% of US/UK patients. The EFS and OS for Brazilian compared with US/UK cohort was stage I: 88% versus 98% (p = .05), stage II-IV EFS: 67% versus 79% (p = .32), stage II-IV OS: 93% versus 97% (p = .44); amongst grade-3 patients, there was no difference in EFS or OS. CONCLUSION: Addition of postoperative chemotherapy did not improve outcome in children with ovarian IT, even at higher grade or stage, compared with surgery alone.

The impact of vincristine on testicular development and function in childhood cancer.

BACKGROUND: Increasing childhood cancer survival rates in recent decades have led to an increased focus on fertility as a long-term complication of cancer treatment. Male childhood cancer survivors often face compromised testicular function as a late effect of chemotherapy exposure, with no well-established options to prevent such damage and subsequent infertility. Despite vincristine being considered to be associated with low-gonadotoxic potential, in prepubertal rodents, it was recently shown to result in morphological alterations of the testis and in severely impaired fertility. OBJECTIVE AND RATIONALE: This systematic review aimed to evaluate the effects of vincristine-containing regimens on human prepubertal testis with reference to testicular function and fertility in adulthood. SEARCH METHODS: The systematic search of the literature was conducted according to PRISMA guidelines, and the study was registered with PROSPERO. PubMed and Scopus were searched for articles published in English between 01 January 1900 and 05 March 2021, with the search including 'chemotherapy', 'vincristine', 'prepubertal', 'testis', 'spermatogenesis' and related terms. Abstracts and full-text articles were screened and selected for, providing they met the inclusion criteria (≤12 years at treatment, exposure to vincristine-containing regimens and long-term fertility outcomes). Additional studies were identified via bibliography screening. Bias evaluation across included studies was conducted using the ROBINS-I tool, subdivided into assessment for confounding, participant selection, intervention classification, missing data, outcome measurements and selection of reported results. OUTCOMES: Our initial search identified 288 articles of which 24 (8%; n = 7134 males) met all inclusion criteria. Control groups were included for 9/24 (38%) studies and 4/24 (17%) studies provided sub-analysis of the relative gonadotoxicity of vincristine-based agents. Primary outcome measures were: fertility and parenthood; semen analysis (World Health Organization criteria); and hormonal function and testicular volume. For the studies that performed vincristine sub-analysis, none reported negative associations with vincristine for the potential of siring a pregnancy, including the largest (n = 6224; hazard ratio = 0.56) controlled study. For semen analysis, no significant difference versus healthy controls was illustrated for mitotic inhibitors (including vincristine) following sub-analysis in one study (n = 143). For hormone analysis, a single study did not find significant impacts on spermatogenesis attributed to vincristine based on levels of FSH and semen analysis, which meant that its administration was unlikely to be responsible for the diminished testicular reserve; however, most of the studies were based on low numbers of patients receiving vincristine-containing chemotherapy. Analysis of bias demonstrated that studies which included vincristine exposure sub-analysis had a lower risk of bias when compared with cohorts which did not. WIDER IMPLICATIONS: In contrast to recent findings in rodent studies, the limited number of clinical studies do not indicate gonadotoxic effects of vincristine following prepubertal exposure. However, given the relative lack of data from studies with vincristine sub-analysis, experimental studies involving vincristine exposure using human testicular tissues are warranted. Results from such studies could better inform paediatric cancer patients about their future fertility and eligibility for fertility preservation before initiation of treatment.

Inconsistencies in fertility preservation for young people with cancer in the UK.

OBJECTIVE: To assess the utilisation of and funding structure for fertility preservation for children diagnosed with cancer in the UK. DESIGN: Survey of paediatric oncologists/haematologists. Questionnaires were sent electronically with reminder notifications to non-responders. SETTING: UK Paediatric Oncology Principal Treatment Centres (PTCs). PARTICIPANTS: Paediatric oncologists/haematologists with an interest in the effects of treatment on fertility representing the 20 PTCs across the UK. MAIN OUTCOME MEASURES: Referral practices, sources and length of funding for storage of gametes or gonadal tissue for children diagnosed with cancer in the preceding 12 months. RESULTS: Responses were received from 18 PTCs (90%) with responses to 98.3% of questions. All centres had referred patients for fertility preservation: ovarian tissue collection/storage 100% (n=18 centres), sperm banking 100% (n=17; one centre was excluded due to the age range of their patients), testicular tissue storage 83% (n=15), mature oocyte collection 35% (n=6; one centre was excluded due to the age range of their patients). All centres with knowledge of their funding source reported sperm cryopreservation was NHS funded. Only 60% (n=9) centres reported the same for mature oocyte storage. Of the centres aware of their funding source, half reported that ovarian and testicular tissue storage was funded by charitable sources; this increased in England compared with the rest of the UK. CONCLUSIONS: Inequality exists in provision of fertility preservation for children with cancer across the UK. There is lack of formalised government funding to support international guidelines, with resultant geographical variation in care. Centralised funding of fertility preservation for children and young adults is needed alongside establishment of a national advisory panel to support all PTCs.

Multicentre service evaluation of presentation of newly diagnosed cancers and type 1 diabetes in children in the UK during the COVID-19 pandemic.

Background: The COVID-19 pandemic led to changes in patterns of presentation to emergency departments. Child health professionals were concerned that this could contribute to the delayed diagnosis of life-threatening conditions, including childhood cancer (CC) and type 1 diabetes (T1DM). Our multicentre, UK-based service evaluation assessed diagnostic intervals and disease severity for these conditions. Methods: We collected presentation route, timing and disease severity for children with newly diagnosed CC in three principal treatment centres and T1DM in four centres between 1 January and 31 July 2020 and the corresponding period in 2019. Total diagnostic interval (TDI), patient interval (PI), system interval (SI) and disease severity across different time periods were compared. Results: For CCs and T1DM, the route to diagnosis and severity of illness at presentation were unchanged across all time periods. Diagnostic intervals for CCs during lockdown were comparable to that in 2019 (TDI 4.6, PI 1.1 and SI 2.1 weeks), except for an increased PI in January-March 2020 (median 2.7 weeks). Diagnostic intervals for T1DM during lockdown were similar to that in 2019 (TDI 16 vs 15 and PI 14 vs 14 days), except for an increased PI in January-March 2020 (median 21 days). Conclusions: There is no evidence of diagnostic delay or increased illness severity for CC or T1DM, during the first phase of the pandemic across the participating centres. This provides reassuring data for children and families with these life-changing conditions.

Micronutrient status influences clinical outcomes of paediatric cancer patients during treatment: A prospective cohort study.

BACKGROUND: Research reporting plasma micronutrient status and its impact on clinical outcomes in paediatric cancer is scarce. Therefore, we investigated the prevalence of plasma micronutrient abnormalities and their impact on clinical outcomes and treatment complications. METHODS: A multicentre prospective-cohort study of children aged <18 years diagnosed with cancer was performed between Aug 2010-Jan 2014. Clinical and nutritional data were collected at diagnosis, 3, 6, 9, 12 and 18 months. Micronutrient status was established using in-house laboratory references (vitamin B12, vitamin A and Vitamin E/Ch) and aged adjusted Z-scores (Mg, Se, Zn and Cu) generated from a cohort of healthy Scottish children. Clinical outcomes were classified as "event free survival (EFS)" or "event" (relapse, death, new metastasis or becoming palliative) and treatment complications. Descriptive statistics, logistic regression and multilevel analysis were performed. RESULTS: Eighty-two patients [median (IQR) 3.9 (1.9-8.8) years, 56% males] were recruited. Of these, 72 (88%) samples were available, 74% (53/72) patients had micronutrient abnormalities at baseline; deficiencies (25%, 18/72), excesses (19%, 14/72) and a combination of both (29%, 21/72), which continued for 18 months. Vitamin A deficiency (15%, 3/20) and excess (50%, 10/20) were most prevalent at 18 months, whilst vitamin E/Cholesterol and vitamin B12 were mostly within the normal range. Prevalence of Zn deficiency at diagnosis was 36% (16/44 adjusted for CRP), which remained at these levels throughout the study. Reduction in each selenium concentration unit increased the odds of an event by 2% (OR 0.02) and lower Se predicted higher complications at diagnosis [ß (-1.2); t (-2.1); 95% CI (-2.9 - (-0.04)); p = 0.04], 3 months [ß (-3.9); t (-4.2); 95% CI (-5.57 - (-2.02)); p < 0.001] and 12 months [ß (-2.3); t (-2.4); 95% CI (-4.10 - (-0.34)); p = 0.02]. CONCLUSIONS: Given the prevalence of micronutrient abnormalities and the negative impact of low selenium on clinical outcome, micronutrient status should be assessed and monitored in paediatric cancer patients. Larger multicentre population based studies and clinical trials are now warranted.

Impacts of platinum-based chemotherapy on subsequent testicular function and fertility in boys with cancer.

BACKGROUND: Children with cancer often face infertility as a long-term complication of their treatment. For boys, compromised testicular function is common after chemotherapy and currently there are no well-established options to prevent this damage. Platinum-based agents are used to treat a wide variety of childhood cancers. However, platinum agents are not currently included in the cyclophosphamide equivalent dose (CED), which is used clinically to assess the risks to fertility posed by combination chemotherapy in children with cancer. OBJECTIVE AND RATIONALE: This was a systematic search of the literature designed to determine the evidence for effects of platinum-based cancer treatment on the prepubertal human testis in relation to subsequent testicular function and fertility. SEARCH METHODS: PubMed and EMBASE were searched for articles published in English between 01 January 1966 and 05 April 2020 using search terms including 'cancer treatment', 'chemotherapy', 'human', 'prepubertal', 'testis', 'germ cells', 'testosterone' and related terms. Abstracts were screened and full-text articles were obtained for those that met the three major inclusion criteria (age ≤12 years at treatment, exposure to platinum-based chemotherapeutic and measure of reproductive function). Screening of bibliographies for full-text articles was used to identify additional studies. OUTCOMES: Our initial search identified 1449 articles of which 20 (1.3%) studies (n = 13 759 males) met all inclusion criteria. A control group (healthy individuals or siblings) was included for 5/20 (25%) studies. A total of 10/20 (50%) studies provided sub-analysis of the relative gonadotoxicity of platinum-based agents.The primary outcome measures were: pregnancies and fatherhood; semen analysis; and hormonal function. For pregnancies and fatherhood, three studies (n = 10 453 males) reported negative associations with platinum-agents, including the largest (n = 5640) controlled study (hazard ratio = 0.56, P = 0.0023), whilst two other studies (n = 1781) with platinum sub-analysis reported no association. For semen analysis (based on World Health Organization criteria), platinum-based chemotherapy was associated with azoospermia in one study (n = 129), whilst another (n = 44) found no association and the remainder did not perform platinum-based sub-analysis. For hormone analysis, conflicting results were obtained regarding potential associations between platinum-based agents and elevated FSH (a proxy for impaired spermatogenesis); however, the majority of these studies were based on low numbers of patients receiving platinum-based chemotherapy. WIDER IMPLICATIONS: Overall, these results indicate that platinum-based chemotherapy should be included in clinical calculators, for example CED, used to determine gonadotoxicity for childhood cancer treatment. These findings have important implications for clinicians regarding counselling patients and their carer(s) on fertility risk, guiding requirements for fertility preservation strategies (e.g. testicular tissue cryopreservation) and modification of treatments to reduce or eliminate the risk of infertility in childhood cancer survivors.

Nutritional screening and assessment of paediatric cancer patients: A quality improvement project (baseline results).

BACKGROUND: The department of Haematology and Oncology at the Royal Hospital for Sick Children (RHSC) in Edinburgh have developed their own nutritional standards specific to paediatric cancer. We aimed to audit the current nutritional practice in anthropometry, nutritional biochemistry and malnutrition screening for paediatric cancer patients against nutritional standards to identify areas for nutritional-practice improvement and progress nutrition-related clinical outcomes. METHODS: A Clinical audit was conducted >20 weeks between 2015 and 2017 in three data collection locations (inpatient (IP), day-care (DC), or outpatient (OP)) at RHSC. We included patients aged 0-18 years and undergoing treatment for diagnosed malignant childhood cancer (ICCC-3 or Langerhans Cell Histiocytosis). Data were collected by analysing documentation and observing clinical practice for frequency and mode of administration of anthropometry, malnutrition screening, nutritional biochemistry and resulting documentation completion. Results were presented as descriptive statistics and stratified by percentage of standard met (100%, 99-70%, <70%). RESULTS: 185 audited patient records (22 IP, 54 DC and 109 OP) were analysed. The areas which were <70% of the standard were: height and weight documentation for DC; head-circumference for IP; arm anthropometry assessment for all locations; initial PYMS screening and re-screening in IP; malnutrition screening in DC and OP; and initial assessment and re-assessment for serum vitamins D, A, E, B12 and parathyroid hormone levels. CONCLUSION: Baseline nutritional practice was successfully established, identifying areas for practice improvement in the RHSC Paediatric Oncology and Haematology Department; this will be implemented in the next step of the audit to optimise patient care.

Detection of Circulating and Disseminated Neuroblastoma Cells Using the ImageStream Flow Cytometer for Use as Predictive and Pharmacodynamic Biomarkers.

PURPOSE: Circulating tumor cells (CTCs) serve as noninvasive tumor biomarkers in many types of cancer. Our aim was to detect CTCs from patients with neuroblastoma for use as predictive and pharmacodynamic biomarkers. EXPERIMENTAL DESIGN: We collected matched blood and bone marrow samples from 40 patients with neuroblastoma to detect GD2 +/CD45- neuroblastoma CTCs from blood and disseminated tumor cells (DTCs) from bone marrow using the Imagestream Imaging flow cytometer (ISx). In six cases, circulating free DNA (cfDNA) extracted from plasma isolated from the CTC sample was analyzed by high-density single-nucleotide polymorphism (SNP) arrays. RESULTS: CTCs were detected in 26 of 42 blood samples (1-264/mL) and DTCs in 25 of 35 bone marrow samples (57-291,544/mL). Higher numbers of CTCs in patients with newly diagnosed, high-risk neuroblastoma correlated with failure to obtain a complete bone marrow (BM) metastatic response after induction chemotherapy (P < 0.01). Ex vivo Nutlin-3 (MDM2 inhibitor) treatment of blood and BM increased p53 and p21 expression in CTCs and DTCs compared with DMSO controls. In five of six cases, cfDNA analyzed by SNP arrays revealed copy number abnormalities associated with neuroblastoma. CONCLUSIONS: This is the first study to show that CTCs and DTCs are detectable in neuroblastoma using the ISx, with concurrently extracted cfDNA used for copy number profiling, and may be useful as pharmacodynamic biomarkers in early-phase clinical trials. Further investigation is required to determine whether CTC numbers are predictive biomarkers of BM response to first-line induction chemotherapy.

Embryonal precursors of Wilms tumor.

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the H19 locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.

Nutritional status of children and adolescents with cancer in Scotland: A prospective cohort study.

BACKGROUND AND AIMS: Malnutrition (under and overnutrition) in paediatric cancer patients during and after treatment increases short and long-term side-effects; however, factors contributing to malnutrition and patterns of change in nutritional status are still unclear. The aims were to investigate the prevalence of malnutrition, patterns of change in nutritional status and factors contributing to malnutrition in Scottish paediatric cancer patients. METHODS: A prospective cohort study of Scottish children aged <18 years, diagnosed with and treated for cancer between Aug 2010 and Jan 2014 was performed. Clinical and nutritional data were collected at defined periods up to 36 months. Measurements of weight and height/length and arm anthropometry (mid-upper arm circumference (MUAC) and triceps skin-fold thickness (TSF)) were collected. Body composition was estimated from arm anthropometry using Frisancho's references and bio-electrical impedance (BIA). Malnutrition was defined according to UK BMI curves; undernutrition (<2.3rd centile; -2 SD), overweight (≥85th < 95th centile; ≥+1.05 SD < 1.63 SD) and obese (≥95th centile; ≥1.63 SD). We performed descriptive statistics and multilevel analysis. p < 0.05 was considered statistically significant. RESULTS: Eighty-two patients [median (IQR) age 3.9 (1.9-8.8) years; 56% males] were recruited. At diagnosis, the prevalence of undernutrition was 13%, overweight 7% and obesity 15%. TSF identified the highest prevalence of undernutrition (15%) and the lowest of obesity (1%). BMI [p < 0.001; 95% CI (1.31-3.47)] and FM (BIA) [p < 0.05; 95% CI (0.006-0.08)] significantly increased after 3 months of treatment, whilst FFM (BIA) [p < 0.05; 95% CI (-0.78 to (-0.01))] significantly decreased during the first three months and these patterns remained until the end of the study. High-treatment risk significantly contributed to undernutrition during the first three months of treatment [p = 0.04; 95% CI (-16.8 to (-0.4))] and solid tumours had the highest prevalence of undernutrition [BMI (17%)]. CONCLUSIONS: Arm anthropometry (or BIA) alongside appropriate nutritional treatment that targets undernutrition initially and overnutrition at later stages should be implemented in routine clinical practice of paediatric cancer patients.

Comparison of carboplatin versus cisplatin in the treatment of paediatric extracranial malignant germ cell tumours: A report of the Malignant Germ Cell International Consortium.

PURPOSE: To compare the outcomes of paediatric and adolescent extracranial malignant germ cell tumour (GCT) patients treated with either carboplatin or cisplatin on clinical trials conducted by the Children's Oncology Group (COG) and the Children's Cancer and Leukaemia Group (CCLG). METHODS: The Malignant Germ Cell International Consortium (MaGIC) has created a database of the GCT clinical trials conducted since 1983 by COG (United States, Canada and Australia), which used cisplatin-based regimens, and by CCLG (United Kingdom), which used carboplatin-based regimens. Using the parametric cure model, this study compared the overall 4-year event-free survival (EFS), stratified by age, stage, site and the a-priori defined MaGIC 'risk' groups: standard risk ((SR) 1 (EFS >80%; age <11 years), SR2 (EFS >80%, age ≥ 11y) and poor risk (PR) (EFS ≤ 70%, age ≥ 11y). RESULTS: Cisplatin-based therapy was used in 620 patients; carboplatin was used in 163 patients. In the overall multivariate cure model, the two regimens did not differ significantly (cisplatin: 4-year EFS 86%; 95% confidence interval (CI) 83-89% versus carboplatin 4-year EFS 86%; 95% CI 79-90%; p = 0.87). No significant differences were noted in stratified analyses by site, stage, age and MaGIC risk groups: SR1 (p = 0.20), SR2 (p = 0.55) or PR (p = 0.72) patients. CONCLUSIONS: In these trials conducted contemporaneously, there is no significant difference in outcome observed overall, or any subset of patients, who were treated with regimens containing cisplatin versus carboplatin These results suggested sufficient equipoise to justify a randomised trial to evaluate the effectiveness of carboplatin versus cisplatin in the treatment of children, adolescents and young adults with standard risk GCT, which is currently underway.

Delayed diffuse cerebellar swelling after resection of medulloblastoma: case report and review of literature.

INTRODUCTION: Delayed diffuse cerebellar swelling is a rare life-threatening complication following medulloblastoma resection. PRESENTATION: We present our experience of managing a 4-year-old who developed diffuse cerebellar swelling with upward herniation 41 days after resection of a large cell anaplastic medulloblastoma. CONCLUSION: Emergency chemotherapy alone was sufficient in promoting regression of swelling and recovery from coma. Reports of similar cases are scant. Chemotherapy may be a critical component of treatment.

5-Hydroxyvitamin D concentration in paediatric cancer patients from Scotland: a prospective cohort study.

Children with cancer are potentially at a high risk of plasma 25-hydroxyvitamin D (25(OH)D) inadequacy, and despite UK vitamin D supplementation guidelines their implementation remains inconsistent. Thus, we aimed to investigate 25(OH)D concentration and factors contributing to 25(OH)D inadequacy in paediatric cancer patients. A prospective cohort study of Scottish children aged 75 nmol/l). In all, eighty-two patients (median age 3·9, interquartile ranges (IQR) 1·9-8·8; 56 % males) and thirty-five controls (median age 6·2, IQR 4·8-9·1; 49 % males) were recruited. 25(OH)D inadequacy was highly prevalent in the controls (63 %; 22/35) and in the patients (64 %; 42/65) at both baseline and during treatment (33-50 %). Non-supplemented children had the highest prevalence of 25(OH)D inadequacy at every stage with 25(OH)D median ranging from 32·0 (IQR 21·0-46·5) to 45·0 (28·0-64·5) nmol/l. Older age at baseline (R -0·46; P<0·001), overnutrition (BMI≥85th centile) at 3 months (P=0·005; relative risk=3·1) and not being supplemented at 6 months (P=0·04; relative risk=4·3) may have contributed to lower plasma 25(OH)D. Paediatric cancer patients are not at a higher risk of 25(OH)D inadequacy than healthy children at diagnosis; however, prevalence of 25(OH)D inadequacy is still high and non-supplemented children have a higher risk. Appropriate monitoring and therapeutic supplementation should be implemented.

Effects of pediatric cancer and its treatment on nutritional status: a systematic review.

CONTEXT: Malnutrition in pediatric cancer is common worldwide, yet its prevalence and effects on clinical outcomes remain unclear. OBJECTIVE: The aim of this review was to evaluate primary research reporting the prevalence of malnutrition in pediatric cancer patients and to assess the effects of pediatric cancer and its treatment on nutritional status. DATA SOURCES: Electronic databases of MEDLINE, CINHAL, and PubMed were searched (January 1990-February 2013). STUDY SELECTION: Studies of patients aged <18 years who were diagnosed with and treated for cancer and for whom measurements of anthropometry were reported and included. The primary outcome was the prevalence of malnutrition (undernutrition and overnutrition), expressed as body mass index (BMI), in children diagnosed with and treated for cancer. DATA EXTRACTION: Evidence was appraised critically by employing the Critical Appraisal Skills Program tool, and data was extracted from original articles. DATA SYNTHESIS: A total of 46 studies were included, most of which were considered to be of low quality on the basis of heterogeneity in both the criteria and the measurements used to define malnutrition. Undernutrition was identified by measuring BMI, weight loss, mid-upper arm circumference, and triceps skinfold thickness, while overnutrition was assessed using BMI. Overall, the prevalence of undernutrition ranged from 0% to 65% and overnutrition from 8% to 78%. Finally, undernutrition in pediatric cancer at diagnosis was associated with poor clinical outcomes in 6 of 9 studies. CONCLUSION: The possibility of a high prevalence of malnutrition in childhood cancer, indicated by the studies reviewed, highlights the need for high-quality, population-based, longitudinal studies using standard criteria to identify malnutrition.

Anti-Müllerian hormone is a marker of gonadotoxicity in pre- and postpubertal girls treated for cancer: a prospective study.

CONTEXT: Cytotoxic treatment may accelerate depletion of the primordial follicle pool, leading to impaired fertility and premature menopause. Assessment of ovarian damage in prepubertal girls is not currently possible, but Anti-Müllerian Hormone (AMH) is a useful marker of ovarian reserve in adults. OBJECTIVE: The objective of the study was to prospectively evaluate AMH measurement in children as a marker of ovarian toxicity during cancer treatment. DESIGN AND SETTING: This was a prospective, longitudinal study at a University Hospital. PATIENTS: Twenty-two females (17 prepubertal), median age 4.4 yr (range 0.3-15 yr), were recruited before treatment for cancer. MAIN OUTCOME MEASURES: AMH, inhibin B, and FSH at diagnosis, after each chemotherapy course and during follow-up, were measured. Risk of gonadotoxicity was classified as low/medium (n = 13) or high (n = 9) based on chemotherapy agent, cumulative dose, and radiotherapy involving the ovaries. RESULTS: Pretreatment AMH was detectable across the age range studied. AMH decreased progressively during chemotherapy (P < 0.0001) in both prepubertal and pubertal girls, becoming undetectable in 50% of patients, with recovery in the low/medium risk groups after completion of treatment. In the high-risk group, AMH became undetectable in all patients and showed no recovery. Inhibin B was undetectable in most patients before treatment and, with FSH, showed no clear relationship to treatment. CONCLUSION: AMH is detectable in girls of all ages and falls rapidly during cancer treatment in both prepubertal and pubertal girls. Both the fall during treatment and recovery thereafter varied with risk of gonadotoxicity. AMH is therefore a clinically useful marker of damage to the ovarian reserve in girls receiving treatment for cancer.

Subfertility in children and young people treated for solid and haematological malignancies.

Children treated for cancer may exhibit impaired fertility in later life. A number of chemotherapeutic agents have been identified as being gonadotoxic, and certain treatment regimens are particularly associated with subsequent infertility. Radiotherapy can also cause gonadal damage, most notably after direct testicular or pelvic irradiation or following total body irradiation. Because of the varied nature of the cytotoxic insult, it can be difficult to predict the likelihood of infertility in later life. Currently, cryopreservation of spermatozoa, oocytes or embryos is the only method of preserving fertility in patients receiving gonadotoxic therapy. This is only applicable to postpubertal patients and can be problematic in the adolescent age group. At present there is no provision for the prepubertal child, although there are a number of experimental methods being investigated. However, in addition to the many scientific and technical issues to be overcome before clinical application of such techniques, a number of ethical and legal issues must also be addressed to ensure a safe and realistic prospect for future fertility in these patients.

Male fertility following childhood cancer: current concepts and future therapies.

Prepubertal boys treated for cancer may exhibit impaired fertility in later life. A number of chemotherapeutic agents have been identified as being gonadotoxic, and certain treatment regimens, such as that used for Hodgkin's disease, are particularly associated with subsequent infertility. Radiotherapy may also cause gonadal damage, most notably following direct testicular irradiation or total body irradiation. Because of the varied nature of the cytotoxic insult, it can be difficult to predict the likelihood of infertility in later life. Currently it is not possible to detect gonadal damage early due to the lack of a sensitive marker of gonadal function in the prepubertal age group. Semen cryopreservation is currently the only method of preserving fertility in patients receiving gonadotoxic therapy. This is only applicable to postpubertal patients and can be problematic in the adolescent age group. At present there is no provision for the prepubertal boy, although there are a number of experimental methods currently being investigated. By harvesting testicular tissue prior to gonadotoxic therapy, restoration of fertility could be achieved following treatment, either by germ cell transplantation or by in vitro maturation of the germ cells harvested. Alternatively, rendering the testes quiescent during cytotoxic treatment may protect the germ cells from subsequent damage. In addition to the many scientific and technical issues to be overcome prior to clinical application of these techniques, a number of ethical and legal issues must also be addressed to ensure a safe and realistic prospect for future fertility in these patients.

The late endocrine effects of childhood cancer treatment.

Whilst many children diagnosed with cancer can now realistically hope for long term survival, the consequences of cancer treatment can be particularly devastating as they enter adolescence and adulthood. Disruption of the endocrine system can result from such treatment, including growth hormone deficiency, problems in normal pubertal progression and thyroid dysfunction. Fertility can also be affected by cancer treatment received as a child, which can have a devastating impact as the patient enters adulthood. In addition, these children may encounter disorders of growth and bone metabolism due to both their initial disease and aspects of its treatment, resulting in further morbidity in later life. The aetiology and diagnosis of these problems are discussed in this review, along with therapeutic options in order to reduce their impact. Long term follow up and clinical vigilance in this patient group is vital. We must continue to strive towards improved survival from childhood cancer, but equally we must remain aware of the adverse effects of treatment, particularly in the long term, and must aim to reduce the impact of these effects as children enter adolescence and adult life.