Sara Stoneham

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.

Pediatric and Adolescent Extracranial Germ Cell Tumors: The Road to Collaboration

During the past 35 years, survival rates for children with extracranial malignant germ cell tumors (GCTs) have increased significantly. Success has been achieved primarily through the application of platinum-based chemotherapy regimens; however, clinical challenges in GCTs remain. Excellent outcomes are not distributed uniformly across the heterogeneous distribution of age, histologic features, and primary tumor site. Despite good outcomes overall, the likelihood of a cure for certain sites and histologic conditions is less than 50%. In addition, there are considerable long-term treatment-related effects for survivors. Even modest cisplatin dosing can cause significant long-term morbidities. A particular challenge in designing new therapies for GCT is that a variety of specialists use different risk stratifications, staging systems, and treatment approaches for three distinct age groups (childhood, adolescence, and young adulthood). Traditionally, pediatric cancer patients younger than 15 years have been treated by pediatric oncologists in collaboration with their surgical specialty colleagues. Adolescents and young adults with GCTs often are treated by medical oncologists, urologists, or gynecologic oncologists. The therapeutic dilemma for all is how to best define disease risk so that therapy and toxicity can be appropriately reduced for some patients and intensified for others. Further clinical and biologic insights can only be achieved through collaborations that do not set limitations by age, sex, and primary tumor site. Therefore, international collaborations, spanning different cooperative groups and disciplines, have been developed to address these challenges.

Successful introduction and audit of a step-down oral antibiotic strategy for low risk paediatric febrile neutropaenia in a UK, multicentre, shared care setting

PURPOSE Patients with febrile neutropaenia (FN) can be stratified according to their risk of significant complications, allowing reduced intensity therapy for low risk (LR) episodes. Serious events are very rare in low risk episodes making randomised trials difficult. Introduction of new evidence-based guidelines followed by re-auditing of the outcome is an alternative strategy. METHODS New guidelines for the management of LR FN were implemented in 4 specialist paediatric oncology centres (POCs) and in their associated shared care units (POSCUs). All patients commenced empirical intravenous antibiotic therapy and after 48h those with blood culture negative episodes designated LR were eligible for discharge on oral co-amoxiclav. Prospective data collection on FN episodes in all treatment centres was undertaken over a 1-year period. RESULTS Seven hundred and sixty two eligible episodes of FN were recorded in 368 patients; 213 episodes were initiated in POCs and 549 episodes were initiated in POSCUs. In 40% of episodes no clinical or microbiological focus of infection was found. At 48h, 212 (27%) episodes were classified as LR and 143 of these (19%) were managed on the LR protocol. There was a low hospital readmission rate (8/143 episodes; 5.6%), no intensive care admissions and no deaths in LR episodes. Almost all LR episodes (209/212) occurred in the shared care setting. CONCLUSIONS Rapid step-down to oral antibiotics was a feasible and safe management strategy for LR FN in the shared care setting in England.

Outcome after autologous hemopoietic stem cell transplantation in relapsed or refractory childhood Hodgkin disease

Objectives: To determine the clinical outcome and prognostic factors for overall survival in children with recurrent and/or primary refractory Hodgkin disease (HD) after high-dose therapy and autologous hemopoietic stem cell transplantation (AHSCT). The survival outcome of this treatment was compared with conventional salvage therapy without stem cell transplantation. Methods: Clinical records of 51 patients with relapsed or refractory HD who underwent AHSCT were reviewed. The source of the stem cells was bone marrow (n = 22) or peripheral blood (n = 29). At the time of high-dose therapy, 39 patients were in complete remission and 1 was in partial remission, while the remaining 11 had refractory disease. The records of 78 patients from the HD 1 trial who underwent conventional salvage treatment but without AHSCT for relapsed or refractory HD were also reviewed. All patients received HDTwithout radiation for conditioning. Results: Overall survival from diagnosis of patients treated with AHSCT did not differ significantly from that of those treated with conventional salvage therapy (hazard ratio = 1.5; 95% confidence interval = 0.9-8.2; P = 0.4). There were also no statistically significant differences in survival data between the two approaches for patients whose duration of first remission was less than or greater than 1 year (P = 0.5; stratified log-rank). Of the 11 patients who received AHSCT for refractory disease, 9 remain alive and well with followups ranging from 2 to 18 years. No deaths due to treatment-related complications were seen in the AHSCT group. Conclusions: Stem cell transplantation does not offer any significant survival advantage over conventional salvage therapy in children with relapsed HD, although it may be of benefit for patients with primary refractory disease.

Peer mentoring: evaluation of a novel programme in paediatrics

Background Mentoring is important for personal and professional development of doctors. Peer mentoring is a core skill in the UK paediatric postgraduate curriculum. However, there is a paucity of peer mentoring programmes aimed at postgraduate doctors in training (postgraduate trainees), and there are no such schemes within paediatrics described in the literature. We developed a regional peer mentoring programme for postgraduate trainees in paediatrics to assess demand and need for peer mentoring and to explore the benefits for both peer mentees and mentors. Programme design Junior postgraduate trainees, randomly selected from volunteers, received peer mentoring from more senior trainees for 1 year. Peer mentors were selected by competitive application and undertook tailored training followed by an experiential learning programme. The programme was evaluated using structured questionnaires. Results 90% (76/84) of first-year postgraduate trainees in paediatrics applied to participate, demonstrating high demand. 18 peer mentor–mentee pairs were matched. Peer mentors and mentees reported high satisfaction rates, acquisition of new and transferable skills and changed behaviours. All peer mentors intended to use the skills in their workplace and, later, as an educational supervisor. Conclusions Our programme represents a novel approach to meeting the demonstrated demand and the curriculum requirement for peer mentoring, and enabled peer mentors and mentees to develop a valuable and versatile skill set. To our knowledge, it is the first such programme in paediatrics and provides a feasibility model that may be adapted locally to allow education providers to offer this important experience to postgraduate trainees.

Is adjuvant chemotherapy indicated in ovarian immature teratomas? A combined data analysis from the Malignant Germ Cell Tumor International Collaborative

There is a debate regarding the management of ovarian immature teratomas (ITs). In adult women, postoperative chemotherapy is standard except for stage I, grade 1 disease, whereas surgery alone is standard in pediatric patients. To determine the role of chemotherapy, a pooled analysis of pediatric and adult clinical trials was conducted.

18F-fluoroethylcholine (18F-Cho) PET/MRI functional parameters in pediatric astrocytic brain tumors.

Purpose To examine the feasibility of simultaneous acquisition of 18F-fluoroethylcholine (18F-choline) PET and functional MRI (standardized uptake value [SUV]max/mean and apparent diffusion coefficient [ADC]mean), using a hybrid PET/MRI scanner, for diagnosis and response assessment in a cohort of children with astrocytic brain tumors. Methods 18F-choline PET/MRI scans were performed in 12 patients with proven astrocytic tumors. Eight patients simultaneously underwent 18F-choline PET/MR follow-up scans after treatment. Uptake in the lesion above the normal brain activity was considered indicative of a positive scan. Maximum and mean SUVs (SUVmax and SUVmean) and mean ADC (ADCmean) of the whole tumor region of interest were assessed. Lesion size and contrast enhancement were recorded. For all tumors, the association between ADCmean and SUVmean/SUVmax values were assessed using the Spearman correlation coefficient. Results At baseline, the areas of 18F-choline uptake matched areas of contrast enhancement and restricted diffusion. There was a negative correlation trend between SUVmax and ADCmean and a positive correlation trend between SUVmax and tumor size. There was concordance between reduction in tumor size and reductions in SUVmax and SUVmean in 4 children, in three of whom ADCmean values were increased. In 2 patients, tumor size remained stable whereas SUVmax and SUVmean values were increased with reduction in the ADCmean values. Additionally, in 2 children, cross-sectional MRI showed an increase both in tumor size and SUVmax but a reduction in ADC values. Conclusions Simultaneous 18F-choline PET/MRI is a promising and reliable imaging tool for children with astrocytic tumors, as it permits monitoring of morphological and metabolic response and changes during therapy.

Treatment and outcome of patients with relapsed clear cell sarcoma of the kidney: a combined SIOP and AIEOP study

Background:Clear cell sarcoma of the kidney (CCSK) is an uncommon paediatric renal tumour. Relapses occur in about 15% of the patients. Since detailed clinical information on relapsed CCSK is scarce, the current study aims to describe outcome of patients with relapsed CCSK treated according to recent European protocols.Patients and methods:We analysed prospectively collected data of all CCSK patients who developed a relapse after complete remission at the end of primary treatment, entered onto SIOP and AIEOP trials between 1992 and 2012.Results:Thirty-seven of 237 CCSK patients (16%) treated according to SIOP and AIEOP protocols developed a relapse. Median time from initial diagnosis to relapse was 17 months (range, 5.5 months - 6.6 years). Thirt-five out of thirty-seven relapses (95%) were metastatic; the most common sites of relapse were the brain (n=13), lungs (n=7) and bone (n=5). Relapse treatment consisted of chemotherapy (n=30), surgery (n=19) and/or radiotherapy (n=18), followed by high-dose chemotherapy and autologous bone marrow transplantation (ABMT) in 14 patients. Twenty-two out of thirty-seven patients (59%) achieved a second complete remission (CR); 15 of whom (68%) developed a second relapse. Five-year event-free survival (EFS) after relapse was 18% (95% CI: 4%–32%), and 5-year overall survival (OS) was 26% (95% CI: 10%–42%).Conclusions:In this largest series of relapsed CCSK patients ever described, overall outcome is poor. Most relapses are metastatic and brain relapses are more common than previously recognised. Intensive treatment aiming for local control, followed by high dose chemotherapy and ABMT, seems to be of benefit to enhance survival. Novel development of targeted therapy is urgently required.

Adolescents and Young Adults With a “Rare” Cancer: Getting Past Semantics to Optimal Care for Patients With Germ Cell Tumors

Because the tumors of adolescence and young adulthood (AYA) are distinct from those that occur earlier and later in life, the most common tumors in this age group are termed “rare.” We offer a collaborative, cross-disciplinary, evidence-based approach, advocated and funded by civil society, to advance the field of germ cell tumor and potentially to apply to other rare AYA tumors.

Evaluation of treatment response using integrated 18F-labeled choline positron emission tomography/magnetic resonance imaging in adolescents with intracranial non-germinomatous germ cell tumours

The efficacy of hybrid 18F‐Fluroethyl‐Choline (FEC) positron emission tomography (PET)/magnetic resonance imaging (MRI) was investigated as an imaging modality for diagnosis and assessment of treatment response and remission status in four patients with proven or suspected intracranial non‐germinomatous germ cell tumours (NGGCT). In two patients faint or absent choline avidity correlated with negative histology, whereas in other two patients, persistent choline avidity in the residual mass was suggestive of presence of viable tumour, subsequently confirmed histologically. We conclude that FEC‐PET/MRI may be an effective imaging tool in detecting viable residual tumour in patients with intracranial NGGCT post treatment. Pediatr Blood Cancer 2015;62:1661–1663.