Juliet Hale

Male and female experiences of having fertility matters raised alongside a cancer diagnosis during the teenage and young adult years.

Discussion and management of potential reproductive health sequelae of adolescent cancer are essential and challenging components of care for the multidisciplinary team. Despite this, research has been limited to specific experiences (e.g. sperm banking) or fertility-related concerns of adult survivors. This grounded theory study of 38 male and female survivors of adolescent cancer aged 16-30 years drew on in-depth single interviews to map the range of experiences of being advised that treatment might affect fertility. Strong support for being told at around diagnosis was found regardless of gender, age, incapacity or availability of fertility preservation services. Age and life stage appeared less significant for impact than the perceived level of threat to personal and social well-being. Women were more likely to achieve lower levels of comprehension about the physiological impact, to report later distress from lack of fertility preservation services and to revisit more frequently those decisions made by the few offered fertility preservation. Men found decision making about sperm banking straightforward on the whole and reported satisfaction with having the choice regardless of outcome. Findings suggest that young people can cope with this information alongside diagnosis especially when professional and parental support is proportionate to the particular impact on them.

Sacrococcygeal teratoma over two decades: Birth prevalence, prenatal diagnosis and clinical outcomes

The birth prevalence and malignant tumour recurrence of sacrococcygeal teratoma (SCT) have not been clearly defined. We conducted this study to determine the birth prevalence, prenatal detection rate, frequency of tumour recurrence and outcome of SCT in a population‐based cohort.

Pharmacokinetics of Dactinomycin in a Pediatric Patient Population: a United Kingdom Children's Cancer Study Group Study

Purpose: Dactinomycin (actinomycin D) is an antitumor antibiotic used routinely to treat certain pediatric and adult cancers. Despite concerns over the incidence of toxicity, little is known about the pharmacology of dactinomycin. A study was done to investigate dactinomycin pharmacokinetics in children. Experimental Design: Dactinomycin was administered to 31 patients by bolus i.v. infusion, at doses of 0.70 to 1.50 mg/m2. Plasma concentrations were determined by liquid chromatography-mass spectrometry up to 24 hours after drug administration and National Cancer Institute Common Toxicity Criteria was assessed. Results: Pharmacokinetic data analysis suggested that a three-compartment model most accurately reflected dactinomycin pharmacokinetics. However, there was insufficient data available to fully characterize this model. A median peak plasma concentration (Cmax) of 25.1 ng/mL (range, 3.2-99.2 ng/mL) was observed at 15 minutes after administration. The median exposure (AUC0-6), determined in 16 patients with sampling to 6 hours, was 2.67 mg/L.min (range, 1.12-4.90 mg/L.min). After adjusting for body size, AUC0-6 and Cmax were positively related to dose (P = 0.03 and P = 0.04, respectively). Patients who experienced any level of Common Toxicity Criteria grade had a 1.46-fold higher AUC0-6, 95% confidence interval (1.02-2.09). AUC0-6 was higher in patients <40 kg, possibly indicating a greater toxicity risk. Conclusions: Data presented suggest that dosing of dactinomycin based on surface area is not optimal, either in younger patients in whom the risk of toxicity is greater, or in older patients where doses are capped.

A phase I study in paediatric patients to evaluate the safety and pharmacokinetics of SPI-77, a liposome encapsulated formulation of cisplatin

Pre-clinical studies indicate that cisplatin encapsulated in STEALTH®liposomes (SPI-77) retains anti-tumour activity, but has a much reduced toxicity, compared to native cisplatin. A phase I study was conducted to determine the toxicity and pharmacokinetics of SPI-77 administered to children with advanced cancer not amenable to other treatment. Paediatric patients were treated at doses ranging from 40 to 320 mg m−2by intravenous infusion every 4 weeks. Blood samples taken during, and up to 3 weeks after, administration and plasma and ultrafiltrate were prepared immediately. Urine was collected, when possible, for 3 days after administration. SPI-77 administration was well tolerated with the major toxicity being an infusion reaction which responded to modification of the initial infusion rate of SPI-77. Limited haematological toxicity and no nephrotoxicity were observed. No responses to treatment were seen during the course of this phase I study. Measurement of total plasma platinum showed that cisplatin was retained in the circulation with a half life of up to 134 h, with maximum plasma concentrations approximately 100-fold higher than those reported following comparable doses of cisplatin. Comparison of plasma and whole blood indicated that cisplatin was retained in the liposomes and there was no free platinum measurable in the ultrafiltrate. Urine recovery was less than 4% of the dose administered over 72 h. Results from this phase I study indicate that high doses of liposomal cisplatin can safely be given to patients, but further studies are required to address the issue of reformulation of liposomally bound cisplatin.

Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial

Summary Background We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. Methods EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1–5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030. Findings Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6–76·6); 62·3 months (IQR 46·9–77·1) for the MAP group and 61·1 months (IQR 46·5–75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78–1·23]); hazards were non-proportional (p=0·0003). The most common grade 3–4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. Interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. Funding UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.

Malignant germ cell tumours of childhood: new associations of genomic imbalance

Malignant germ cell tumours (MGCTs) of childhood are a rare group of neoplasms that comprise many histological subtypes and arise at numerous different sites. Genomic imbalances have been described in these tumours but, largely because of the paucity of cases reported in the literature, it is unclear how they relate to abnormalities in adult MGCTs and impact on potential systems for classifying GCTs. We have used metaphase-based comparative genomic hybridisation to analyse the largest series of paediatric MGCTs reported to date, representing 34 primary tumours (22 yolk sac tumours (YSTs), 11 germinomatous tumours and one metastatic embryonal carcinoma) occurring in children from birth to age 16, including 17 ovarian MGCTs. The large dataset enabled us to undertake statistical analysis, with the aim of identifying associations worthy of further investigation between patterns of genomic imbalance and clinicopathological parameters. The YSTs showed an increased frequency of 1p- (P=0.003), 3p+ (P=0.02), 4q− (P=0.07) and 6q− (P=0.004) compared to germinomatous tumours. Gain of 12p, which is invariably seen in adult MGCTs, was present in 53% of primary MGCTs of children aged 5–16 and was also observed in four of 14 YSTs affecting children less than 5. Two of these cases (14% of MGCTs in children less than 5) showed gain of the 12p11 locus considered to be particularly relevant in adult MGCTs. Gain of 12p showed a significant association with gain of 12q. Conversely, MGCTs without 12p gain displayed a significantly increased frequency of loss on 16p (P=0.04), suggesting that this imbalance may contribute to tumour development in such cases. This data provides new insight into the biology of this under-investigated tumour group and will direct future studies on the significance of specific genetic abnormalities.

Treatment of relapsed Wilms tumors: lessons learned

Treatment regimens for recurrent Wilms tumor (WT) are currently designed to include drugs that are not used during primary chemotherapy, using a risk-stratified approach. Therapy of recurrent disease depends on the nature of initial treatment, and of recognized prognostic indicators inherent in the primary tumor. Several highly effective chemotherapy regimens, including ifosfamide–carboplatin–etoposide, cyclophosphamide–etoposide and carboplatin–etoposide, are considered first treatment choice for recurrent disease. While intense-dose chemotherapy is uniformly accepted to treat high-risk recurrent WTs, the optimal therapy for standard-risk children has yet to be defined, owing to the small number of such patients and their relatively better prognosis compared with high-risk recurrences. Recurrent tumors among those defined as very-high risk are likely to develop chemoresistant disease, and novel therapeutic strategies will be necessary to cure these patients. Evidence on how to properly administer surgery and radiotherapy at relapse is more fragmentary. The authors have reviewed the available experiences concerning the treatment of recurrent WT, and have attempted to provide the most up-to-date recommendations regarding the optimal risk-based treatment for these patients.

Revised Risk Classification for Pediatric Extracranial Germ Cell Tumors Based on 25 Years of Clinical Trial Data From the United Kingdom and United States

PURPOSE To risk stratify malignant extracranial pediatric germ cell tumors (GCTs). PATIENTS AND METHODS Data from seven GCT trials conducted by the Childrens Oncology Group (United States) or the Childrens Cancer and Leukemia Group (United Kingdom) between 1985 and 2009 were merged to create a data set of patients with stage II to IV disease treated with platinum-based therapy. A parametric cure model was used to evaluate the prognostic importance of age, tumor site, stage, histology, tumor markers, and treatment regimen and estimate the percentage of patients who achieved long-term disease-free (LTDF) survival in each subgroup of the final model. Validation of the model was conducted using the bootstrap method. RESULTS In multivariable analysis of 519 patients with GCTs, stage IV disease (P = .001), age ≥ 11 years (P < .001), and tumor site (P < .001) were significant predictors of worse LTDF survival. Elevated alpha-fetoprotein (AFP) ≥ 10,000 ng/mL was associated with worse outcome, whereas pure yolk sac tumor (YST) was associated with better outcome, although neither met criteria for statistical significance. The analysis identified a group of patients age > 11 years with either stage III to IV extragonadal tumors or stage IV ovarian tumors with predicted LTDF survival < 70%. A bootstrap procedure showed retention of age, tumor site, and stage in > 94%, AFP in 12%, and YST in 27% of the replications. CONCLUSION Clinical trial data from two large national pediatric clinical trial organizations have produced a new evidence-based risk stratification of malignant pediatric GCTs that identifies a poor-risk group warranting intensified therapy.

A genome-wide association study identifies susceptibility loci for Wilms tumor

Wilms tumor is the most common renal malignancy of childhood. To identify common variants that confer susceptibility to Wilms tumor, we conducted a genome-wide association study in 757 individuals with Wilms tumor (cases) and 1,879 controls. We evaluated ten SNPs in regions significantly associated at P < 5 × 10−5 in two independent replication series from the UK (769 cases and 2,814 controls) and the United States (719 cases and 1,037 controls). We identified clear significant associations at 2p24 (rs3755132, P = 1.03 × 10−14; rs807624, P = 1.32 × 10−14) and 11q14 (rs790356, P = 4.25 × 10−15). Both regions contain genes that are plausibly related to Wilms tumorigenesis. We also identified candidate association signals at 5q14, 22q12 and Xp22.

Neurosurgical management of paediatric germ cell tumours of the central nervous system - a multi-disciplinary team approach for the new millennium

The long term survival for children with tumours of the central nervous system (CNS) has increased steadily over the last 30 years. This has been attributed to improvements in neuro-imaging, peri-operative care including new neurosurgical approaches, and the use of radiotherapy.1 Chemotherapy is also of proven benefit in some CNS tumours, such as primitive neuro-ectodermal tumours and malignant secreting germ cell tumours,2–6 and is now being explored in many other tumour types. However, survival rates for children with leukaemia and non-neurological tumours have risen more,7 and a significant survival benefit in leukaemia has been linked to treatment carried out according to standardized protocols, within clinical trials, and in specialist children’s cancer centres.8 The poorer outcome of brain tumours may be as much to do with biological behaviour as with organization of care but shortcomings in the latter have been identified and addressed in the form of guidelines, developed by representatives of the British Paediatric Neurosurgery Group (BPNG) and United Kingdom Children’s Cancer Study Group (UKCCSG) and promoted by the Department of Health.9 In particular, patterns of referral were not as well defined for brain tumours as for extracranial tumours, selection of patients for referral for adjuvant therapy was idiosyncratic, and the involvement of expert multi-disciplinary teams in diagnosis, treatment and rehabilitation, patchy. The need to incorporate brain tumours into clinical trials in order to gather information about the most effective treatments was also recognised. There has been a steady increase in the percentage of childhood CNS tumours registered with the UKCCSG over the last 15 years (around 40% in 1986, 80% in 1998) and there has been a parallel increase in the availability of clinical trials. Collaboration between the UKCCSG, other national groups, and the International Society of Paediatric Oncology (SIOP) has also led to the development of international studies and, as a result, there are now trials open for most types of primary brain tumour in childhood. Intracranial germ cell tumours (GCTs) are rare tumours of children and adolescents, occurring more commonly in males, and predominantly between the ages of 6 and 14 years.10 They are typically midline tumours, situated either in the suprasellar or pineal region, or sometimes both, and therefore frequently present as neurosurgical emergencies with raised intracranial pressure; a smaller number may present with neuroendocrine symptoms or visual failure due to chiasmatic involvement. CNS GCTs comprise a histologically heterogeneous group; germinomas are characterized by negative tumour markers and are therefore diagnosed by biopsy or cerebro-spinal fluid (CSF) cytology, in the presence of normal serum and CSF levels of a -fetoprotein ( a FP) and b -HCG. An exception to this is a small subgroup of germinomas with slightly raised levels of b -HCG (not greater than 50IU/l) which result from the presence of syncytiotrophoblastic cells and are, by international consensus, consistent with the diagnosis of germinoma.11 The overall survival for germinoma is