Roderick Skinner

Long-term cause-specific mortality among survivors of childhood cancer.

CONTEXT Survivors of childhood cancer are at increased risk of premature mortality compared with the general population, but little is known about the long-term risks of specific causes of death, particularly beyond 25 years from diagnosis at ages when background mortality in the general population starts to increase substantially. OBJECTIVE To investigate long-term cause-specific mortality among 5-year survivors of childhood cancer in a large-scale population-based cohort. DESIGN, SETTING, AND PATIENTS British Childhood Cancer Survivor Study, a population-based cohort of 17,981 5-year survivors of childhood cancer diagnosed with cancer before age 15 years between 1940 and 1991 in Britain and followed up until the end of 2006. MAIN OUTCOME MEASURES Cause-specific standardized mortality ratios (SMRs) and absolute excess risks (AERs). RESULTS Overall, 3049 deaths were observed, which was 11 times the number expected (SMR, 10.7; 95% confidence interval [CI], 10.3-11.1). The SMR declined with follow-up but was still 3-fold higher than expected (95% CI, 2.5-3.9) 45 years from diagnosis. The AER for deaths from recurrence declined from 97 extra deaths (95% CI, 92-101) per 10,000 person-years at 5 to 14 years from diagnosis, to 8 extra deaths (95% CI, 3-22) beyond 45 years from diagnosis. In contrast, during the same periods of follow-up, the AER for deaths from second primary cancers and circulatory causes increased from 8 extra deaths (95% CI, 7-10) and 2 extra deaths (95% CI, 2-3) to 58 extra deaths (95% CI, 38-90) and 29 extra deaths (95% CI, 16-56), respectively. Beyond 45 years from diagnosis, recurrence accounted for 7% of the excess number of deaths observed while second primary cancers and circulatory deaths together accounted for 77%. CONCLUSION Among a cohort of British survivors of childhood cancer, excess mortality from second primary cancers and circulatory diseases continued to occur beyond 25 years from diagnosis.

Ifosfamide, mesna, and nephrotoxicity in children.

PURPOSE With the increasing use of ifosfamide in pediatric malignancies, nephrotoxicity has emerged as a potentially serious adverse effect, which may be dose-limiting or may cause severe chronic morbidity, including glomerular impairment and/or Fanconis syndrome. The purpose of this review was (1) to improve the documentation of ifosfamide nephrotoxicity in children, and (2) to consider the possible causative role of ifosfamide metabolites. DESIGN (1) A grading system was developed that allowed documentation of the nature and severity of published reports of ifosfamide-induced nephrotoxicity, and evaluation of patient and treatment-related risk factors. (2) The relationship between the pharmacology of ifosfamide/mesna and nephrotoxicity was investigated by examination of published data, especially that concerning the quantitative differences in the metabolism of ifosfamide and its nonnephrotoxic structural isomer, cyclophosphamide. RESULTS (1) Examination of 16 published reports (with assessable data from 40 children) demonstrated that ifosfamide-induced nephrotoxicity was associated with a wide range of patient ages and ifosfamide cumulative doses given by different administration schedules. (2) Chloroacetaldehyde, a major metabolite of ifosfamide only, may be at least partly responsible for the renal toxicity of this drug. Although mesna may be capable of detoxifying the toxic metabolite(s), delivery to the renal tubule may not be sufficient to provide adequate protection of tubular glutathione from depletion by the metabolite(s), which results in a failure to prevent nephrotoxicity. CONCLUSION Increased understanding of the interindividual variability in the extent and nature of ifosfamide metabolism, which may be a major determinant of susceptibility to renal damage, may lead to improved use of the drug with less nephrotoxicity.

A Worldwide Collaboration To Harmonize Guidelines For The Long-Term Follow-Up Of Childhood And Young Adult Cancer Survivors: A Report From The International Late Effects Of Childhood Cancer Guideline Harmonization Group

Childhood and young adult cancer survivors should receive optimum care to reduce the consequences of late effects and improve quality of life. We can facilitate achieving this goal by international collaboration in guideline development. In 2010, the International Late Effects of Childhood Cancer Guideline Harmonization Group was initiated. The aim of the harmonization endeavor is to establish a common vision and integrated strategy for the surveillance of late effects in childhood and young adult cancer survivors. With the implementation of our evidence‐based methods, we provide a framework for the harmonization of guidelines for the long‐term follow‐up of childhood and young adult cancer survivors. Pediatr Blood Cancer 2013; 60: 543–549.

Risk factors for nephrotoxicity after ifosfamide treatment in children: a UKCCSG Late Effects Group study

The aim of this multicentre study was to document the nephrotoxicity associated with ifosfamide and evaluate risk factors in 148 children and young people with sarcomas who underwent investigation of renal function on one occasion each, at a median of 6 (range 1–47) months after completion of ifosfamide (median dose 62.0 (range 6.1–165.0) g/m2). Investigations included glomerular filtration rate (GFR), serum bicarbonate (HCO3) and phosphate (PO4), and renal tubular threshold for phosphate (Tmp/GFR). A clinically relevant ‘nephrotoxicity score’ was derived. GFR was < 90 ml/min/1.73 m2in 61 of 123 evaluable patients, Tmp/GFR < 0.9–1.1 mmol/l (age-dependent) in 45/103, serum PO4< 0.9–1.mmol/l (age-dependent) in 28/135, and serum HCO3< 20 (< 18 in infants) mmol/l in 22/95. Of 76 fully evaluable patients: 50% had mild, 20% moderate and 8% severe nephrotoxicity. Higher total ifosfamide dose correlated significantly with greater glomerular and tubular toxicity (P< 0.01); other risk factors, including age at treatment, demonstrated no consistent significant independent effect. Chronic ifosfamide-related glomerular and proximal tubular toxicity were common in this large comprehensive study. Restriction of total ifosfamide dose to < 84 g/m2will reduce the frequency of, but not abolish, clinically significant nephrotoxicity, whilst doses > 119 g/m2are associated with a very high risk of severe toxicity.

Nephrotoxicity after ifosfamide.

Eleven children and adolescents with previously normal renal function who received ifosfamide for the treatment of extrarenal solid tumours underwent detailed investigation of glomerular and renal tubular function to assess the incidence and extent of renal damage. None had received cisplatin. Glomerular filtration rate (measured by plasma clearance of 51Cr labelled edetic acid) was reduced in six children. All 11 patients had evidence of proximal, and six of distal, tubular damage. Proximal tubular toxicity was indicated by phosphaturia and hypophosphataemia (n = 4), glycosuria (n = 5), increased urine beta 2 microglobulin excretion (n = 11), and generalised aminoaciduria (n = 10); distal tubular damage caused a reduction of the osmolality of the urine in an early morning sample. Two children developed clinical hypophosphataemic rickets, and one of these also had severe nephrogenic diabetes insipidus. Glomerular and tubular nephrotoxicity are common and potentially serious complications of ifosfamide treatment in children.

Risk factors for ifosfamide nephrotoxicity in children

BACKGROUND Risk factors for long-term nephrotoxicity after ifosfamide for childhood cancers are not fully known. We have studied patient-related and treatment-related risk factors for chronic ifosfamide nephrotoxicity. METHODS A group of 23 children who had received ifosfamide at age 2.1-16.2 years (median 6.9) for various cancers were assessed for nephrotoxicity, at 1-28 (2) months after the end of treatment, by renal function testing, laboratory values, and a grading score (none, mild, moderate, severe). No patient had received cisplatin or undergone nephrectomy. 13 children were reassessed at 10-26 (23) months; eight had died and two were not evaluable. The median total ifosfamide dose was 100.8 (9.0-160.4) g/m2 over a median of 15 courses every 3 weeks as a 48-72 h continuous intravenous infusion (in 22 cases), with mesna and hydration. FINDINGS Glomerular filtration rate was below normal in ten (45%) of 22 evaluable children; their rate was 61-85 mL/min per 1.73 m2. Proximal tubular toxicity led to hypophosphataemic rickets and/or renal tubular acidosis in six children, and distal tubular toxicity caused nephrogenic diabetes insipidus in one. Of the risk factors analysed by multiple regression, only total ifosfamide dose was associated with proximal tubular toxicity. Only two of ten evaluable patients who received under 100 g/m2 developed moderate nephrotoxicity, whereas six of ten who received over this dose had moderate or severe nephrotoxicity. INTERPRETATION High total ifosfamide dose was the only risk factor we identified. Although inter-patient variability was high, cumulative doses of 100 g/m2 or higher should be avoided in children with cancer.

Persistent nephrotoxicity during 10-year follow-up after cisplatin or carboplatin treatment in childhood: Relevance of age and dose as risk factors

PURPOSE The long-term outcome of platinum-induced nephrotoxicity is unknown. This prospective single-centre longitudinal cohort study evaluated long-term changes following treatment in childhood. METHODS 63 children treated with platinum (27 cisplatin, 24 carboplatin and 12 both) were studied at the end of treatment (End), 1 year and 10 years later. No child received ifosfamide. Glomerular filtration rate (GFR), serum calcium and magnesium (Mg) were measured, and total nephrotoxicity score (N(s)) was graded. RESULTS There was no significant overall change in renal function over time in any treatment group (cisplatin, carboplatin or combined). Apart from marginally reduced median GFR (84 ml/min/1.73 m(2)) and Mg (0.68 mmol/l) at End of cisplatin, median GFR, Ca and Mg were normal at all times in each group. At 10 years, GFR was <60 ml/min/1.7 3m(2) in 11%, N(s) grade was severe in 15% and oral Mg supplements were required in 7% cisplatin patients. After cisplatin, older age at treatment was correlated with lower GFR at 10 years (p=0.005), and higher N(s) at End and 10 years (both p=0.02). After carboplatin treatment, older age was associated with lower GFR at all times, and with higher N(s) at End and 1 year (all p<0.03). Higher cisplatin dose rate (>40 mg/m(2)/day) was associated with higher N(s) at 1 year (p=0.02) and higher carboplatin dose with lower Mg at 1 year and with higher N(s) at 1 and 10 years (all p<0.008). CONCLUSIONS Platinum nephrotoxicity did not change significantly over 10 years. Its severity was correlated to older age at treatment, and at some time points to higher cisplatin dose rate and higher cumulative carboplatin dose.

Health-related quality of life in survivors of BMT for paediatric malignancy : a systematic review of the literature

We review evidence concerning health-related quality of life (HRQL) following paediatric haemopoietic stem cell transplant. The aims are to determine (1) HRQL compared with population norms; (2) changes in HRQL over time and (3) relations between pre-transplant variables (disease, individual and family resources) and survivor HRQL. Five databases were searched for articles published between January 1990 and February 2008. A total of 15 studies including 12 separate cohorts were identified. (1) HRQL was comparable with or better than population norms 6 months to 8 years post transplant. (2) HRQL was already compromised pre-transplant, further impaired immediately following conditioning, but improved 4–12 months post transplant. (3) Pre-transplant predictors of HRQL include family functioning and individual resources (for example, social skills). Identification of pre-transplant variables associated with long-term HRQL is invaluable to inform early psychological intervention and facilitate positive adjustment.

Dose-related nephrotoxicity of carboplatin in children

SummaryThis study investigated changes and the time course of these changes in renal function in children following treatment with carboplatin, and identified risk factors for nephrotoxicity. Glomerular and proximal renal tubular function were investigated before and up to 2 years after treatment in 23 children who received carboplatin. The main findings were reduced glomerular filtration rate (GFR), and increased renal tubular loss of magnesium, manifested by a low serum magnesium (S Mg). The mean fall in GFR was 22 ml min–1 1.73 m–2 (P = 0.012), and in S Mg it was 0.17 mmol l–1 (P = 0.0077). No patient had a clinically important reduction in GFR, and only one patient had symptomatic hypomagnesaemia. GFR and S Mg did not change over time after completion of treatment. Cumulative dose (CD) of carboplatin was inversely related to mean S Mg at the end of treatment (P = 0.031), and directly related to the fall in S Mg (P < 0.001). Calculated cumulative area under the plasma concentration versus time curve (AUC) of carboplatin was inversely related to S Mg after treatment (P = 0.004). Dose intensity (DI) of carboplatin was not shown to be related to S Mg following treatment. CD, AUC and DI of carboplatin were not related to GFR, nor change in GFR, after treatment. High CDs of carboplatin may be associated with evidence of renal damage qualitatively similar to but less severe than that caused by cisplatin. GFR and SMg should be carefully monitored when high CDs of carboplatin are used, or if carboplatin is combined with other nephrotoxic chemotherapy.

Variation in policies for the management of febrile neutropenia in United Kingdom Children’s Cancer Study Group centres

Objective: To assess the variation in the current UK management strategies for the treatment of febrile neutropenia in childhood. Design and setting: A postal survey of all 21 United Kingdom Children’s Cancer Study Group (UKCCSG) centres assessing and collating local policies, protocols or guidelines relating to the management of febrile neutropenia. Further direct contact was undertaken to clarify any uncertainties. Results: All 21 centres provided information. The policies used to manage febrile neutropenia in the centres around the UK vary in almost every aspect of management. Definitions of fever ranged from a persistent temperature of >37.5°C to a single reading of >39°C. Neutropenia was inconsistently defined as an absolute neutrophil count of <1×109, <0.75×109 or <0.5×109. Choices of antibiotic approaches, empirical modifications and antistaphylococcal treatment were different in each protocol. The use of risk stratification was undertaken in 11 centres, with six using a policy of reduced intensity therapy in low risk cases. Empirical antifungal treatment was very poorly described and varied even more widely. Conclusions: There was a great deal of variation in definitions and treatment of febrile neutropenia in the UKCCSG children’s cancer treatment centres. A degree of variation as a result of local microbiological differences is to be expected, but beyond this we should seek to standardise the core of our approach to defining fever and neutropenia, risk stratification and duration of empirical therapy in a way that maintains safety, minimises resource utilisation and maximises quality of life.