Nicky Thorp

The role of surgery in optic pathway/hypothalamic gliomas in children.

OBJECT Optic pathway/hypothalamic gliomas (OPHGs) are generally benign tumors situated in an exquisitely sensitive brain region. The location and natural history of OPHGs has led to much debate about optimal treatment. This paper revisits the role of and optimal timing of debulking surgery in OPHG. METHODS This paper presents a series of cases managed by the neuro-oncology team at Alder Hey Childrens Hospital and a single surgeon. Data were collected retrospectively for periods prior to 2009 and prospectively thereafter. Tailored treatment strategies were used, including observation and combinations of surgery, chemotherapy, and radiotherapy. Tumor control rates and outcomes are reviewed. RESULTS Forty-two patients were treated between 1998 and 2011. Their median age at diagnosis was 5 years 7 months. Nineteen patients were positive for neurofibromatosis Type 1 (NF1) and 23 patients were negative for NF1. The median duration of follow-up was 77 months (range 21.8-142.3 months). Presenting symptoms included visual impairment (in 50% of cases), headache (in 24%), and hypothalamic/pituitary dysfunction (in 29%). Twenty-two debulking procedures were performed in 21 patients. Four biopsies (3 open, 1 endoscopic) were also performed. The histological diagnosis was pilocytic astrocytoma in 21 patients and pilomyxoid astrocytoma in 2 patients. Ten patients (Group 1) had primary surgical debulking alone and were then observed. Four patients (Group 2) had surgical debulking, plus planned chemotherapy within 3 months. Seven patients (Group 3) required surgical debulking for progressive disease following a variety of treatments. Patient age had the greatest impact on subsequent tumor progression. In total, 13 patients received chemotherapy, 4 on initial presentation, 4 in combination with surgery, and 5 for further tumor progression. Five patients were treated with radiotherapy, 3 prior to referral to Alder Hey. Eleven patients required shunt insertion for hydrocephalus. Vision was stabilized for 74% of patients. The number of patients with hypothalamic/pituitary dysfunction increased from 12 at presentation to 16 by the end of treatment. The overall survival rate was 93%. Three patients died-1 from tumor progression, 1 from infective complications from tumor biopsy, and 1 from a spontaneous posterior fossa hemorrhage. NF1 was associated with improved outcome-fewer patients required active intervention and rates of visual impairment and/or or hypothalamic/pituitary dysfunction were lower. CONCLUSIONS Good long-term survival and functional outcomes can be achieved in children with OPHG. Tumor control was achieved through an individualized approach using surgery, chemotherapy, or radiotherapy in varied combinations. The authors aim to limit radiotherapy to cases involving older children in whom other therapies have failed, due to the well-described and often devastating late effects associated with midline cranial irradiation. Surgery has a clear role for diagnosis, tumor control, and relief of mass effect. In particular, primary surgical debulking of tumor (without adjuvant therapy) is safe and effective. Recent advances in intraoperative MRI may add value and need further assessment.

Management strategies for recurrent ependymoma in the paediatric population.

IntroductionThe management of recurrent ependymoma within the paediatric population remains a therapeutic challenge. The options available are varied and patients may have already received prior radio- or chemotherapy. As yet, no consensus exists regarding their optimal treatment. We review the literature and present our contemporary management strategies for this interesting group of patients.Results and discussionSurvival following recurrence is poor and those prognostic factors that predispose to recurrence include extent of surgical resection and the timing of administration of adjuvant therapy. The extent of resection at re-operation can confer a survival advantage, without a necessary increase in morbidity. Strategies aimed at improving surgical resection at first diagnosis include improving and centralising post-surgical radiological review, defining what are true residuals, and centralising surgical review of incompletely resected tumours. Re-irradiation can improve survival, and with the use of conformal radiation fields need not necessarily lead to neuropsychological damage. Cisplatin and etoposide remain the most effective chemotherapeutic agents to date and with an increase in the understanding of tumour biology this may improve further. Because of the complex nature of this group of patients, decisions regarding their management require the involvement of a paediatric neurosurgeon, paediatric neuro-oncologist and paediatric radiation oncologist.

The neuroendocrine sequelae of paediatric craniopharyngioma: a 40-year meta-data analysis of 185 cases from three UK centres

OBJECTIVES The management of paediatric craniopharyngiomas was traditionally complete resection (CR), with better reported tumour control compared to that by partial resection (PR) or limited surgery (LS). The subsequent shift towards hypothalamic sparing, conservative surgery with adjuvant radiotherapy (RT) to any residual tumour aimed at reducing neuroendocrine morbidity, has not been systematically studied. Hence, we reviewed the sequelae of differing management strategies in paediatric craniopharyngioma across three UK tertiary centres over four decades. METHODS Meta-data was retrospectively reviewed over two periods before (1973-2000 (Group A: n = 100)) and after (1998-2011 (Group B: n = 85)) the introduction of the conservative strategy at each centre. RESULTS Patients had CR (A: 34% and B: 19%), PR (A: 48% and B: 46%) or LS (A: 16% and B: 34%), with trends reflecting the change in surgical approach over time. Overall recurrence rates between the two periods did not change (A: 38% vs B: 32%). More patients received RT in B than A, but recurrence rates were similar: for A, 28% patients received RT with 9 recurrences (32%); for B, 62% received RT with 14 recurrences (26%). However, rates of diabetes insipidus (P = 0.04), gonadotrophin deficiency (P < 0.001) and panhypopituitarism (P = 0.001) were lower in B than those in A. In contrast, post-operative obesity (BMI SDS >+2.0) (P = 0.4) and hypothalamic (P = 0.1) and visual (P = 0.3) morbidity rates were unchanged. CONCLUSION The shift towards more conservative surgery has reduced the prevalence of hormone deficiencies, including diabetes insipidus, which can be life threatening. However, it has not been associated with reduced hypothalamic and visual morbidities, which remain a significant challenge. More effective targeted therapies are necessary to improve outcomes.

The UK Experience of a Treatment Strategy for Pediatric Metastatic Medulloblastoma Comprising Intensive Induction Chemotherapy, Hyperfractionated Accelerated Radiotherapy and Response Directed High Dose Myeloablative Chemotherapy or Maintenance Chemotherapy (Milan Strategy)

Historically, the 5‐year overall survival (OS) for metastatic medulloblastoma (MMB) was less than 40%. The strategy of post‐operative induction chemotherapy (IC) followed by hyperfractionated accelerated radiotherapy (HART) and response directed high dose chemotherapy (HDC) was reported in a single center study to improve 5‐year OS to 73%. We report outcomes of this strategy in UK.

The effectiveness and safety of proton beam radiation therapy in children with malignant central nervous system (CNS) tumours: protocol for a systematic review

BackgroundThe aim of this study is to use a systematic review framework to identify and synthesise the evidence on the use of proton beam therapy (PBT) for the treatment of children with CNS tumours and where possible compare this to the use of photon radiotherapy (RT).MethodsStandard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Twelve electronic databases have been searched, and further citation, hand searching and reference checking will be employed. Studies assessing the effects of PBT used either alone or as part of a multimodality treatment regimen in children with CNS tumours will be included. Relevant economic evaluations will also be identified. The outcomes are survival (overall, progression-free, event-free, disease-free), local and regional control rates, short- and long-term adverse events, functional status measures and quality of survival. Two reviewers will independently screen and select studies for inclusion in the review. All interventional study designs will be eligible for inclusion in the review. However, initial scoping searches indicate the evidence base is likely to be limited to case series studies, with no studies of a higher quality being identified. Quality assessment will be undertaken using pre-specified criteria and tailored to study design if applicable. Studies will be combined using a narrative synthesis, with differences in results between studies highlighted and discussed in relation to the patient population, intervention and study quality. Where appropriate, if no studies of a comparative design are identified, outcomes will be compared against a range of estimates from the literature for similar populations and treatment regimens from the best available evidence from studies that include the use of advanced conventional photon therapy.DiscussionThe evidence base for the use of PBT in children with CNS tumours is likely to be relatively sparse, highly heterogeneous and potentially of a low quality with small sample sizes. Furthermore, selection and publication biases may limit the internal and external validity of studies. However, any tentative results from the review on potential treatment effects can be used to plan better quality research studies that are of a design appropriate for outcome comparison with conventional therapy.Systematic review registrationPROSPERO CRD42015029583

Reply to Comment on: The UK Experience of a Treatment Strategy for Pediatric Metastatic Medulloblastoma Comprising Intensive Induction Chemotherapy, Hyperfractionated Accelerated Radiotherapy, and Response-Directed High-Dose Myeloablative Chemotherapy or

To the Editor: We thank Massimino and colleagues [1] for their comments on our paper.[2] Our study was a retrospective audit of survival, toxicity, and deliverability of this regimen in 14 UK centers. It was not our intention to criticize the Milan group’s work.[3] However, it is essential to monitor outcomes when introducing new treatments, especially when these are of high intensity and in high-risk patients. Single-site studies may be influenced by local in-house practice not described in detail in publications. Case selection may also be an issue. Milan is a national referral center, but the UK patients were treated in their local specialist centers. Potentially, patients with more neurological damage who might not have been able to travel to a supraregional center may have been treated on this regimen in the UK. The concerning toxicities seen in our retrospective audit highlight the importance of prospective audit and monitoring of any new treatments that are introduced. Given the rarity of the disease, this needs to take place at a national level, not at an institutional level. Large-scale phase III clinical trials are the gold standard to evaluate promising results from early phase trials. For example, in adult lymphoma, the Southwest Oncology Group (SWOG) trial showed that standard cyclophosphamide, doxorubicin (hydroxydaunomycin), vincristine (Oncovin R ©), prednisolone (CHOP) was actually better than three more complex regimens reported by single institutions to improve cure rates from 30% to 60%.[4] In our series of metastatic medulloblastoma patients treated with the “Milan” regimen, we did not encounter any severe neurotoxicity unlike the series of patients treated for Supratentorial primitive neuroectodermal tumor (sPNETs) in theUK.[5,6] This important issue was included in the discussion of our findings and we described neurotoxicity as rare and not unexpected in our paper. This rarity is also noted in the papers referenced by the authors of the letter.[7–9] The Milan group reference the conclusions of the international workshop[10] convened after clinically significant toxicity became so prominent that it could not be ignored. This workshop was convened after our paper was submitted and aimed at defining possible underlying reasons. However, UK audits of sPNET treated with the same therapy strategy described frequent, clinically devastating global neurotoxicity.[5,6] The combined use of high-dose chemotherapy with radiotherapy seems to have revealed this vulnerability.[6] In conclusion, the introduction of intensified chemoradiotherapy in childhood brain tumors requires an active program of clinical trials. If these are not available, there needs to be an audit of outcomes of national interim guidance shared internationally to learn from the larger number of patients treated. This would highlight the importance of first careful guideline development, second the need for compliance with detailed clinical protocols, and finally prospectively monitored toxicity and outcomes. Adequate funding and resources for such an audit are essential when implementing any regimen across multiple centers at a national level.

SIOPE – Brain tumor group consensus guideline on craniospinal target volume delineation for high-precision radiotherapy

OBJECTIVE To develop a consensus guideline for craniospinal target volume (TV) delineation in children and young adults participating in SIOPE studies in the era of high-precision radiotherapy. METHODS AND MATERIALS During four consensus meetings (Cambridge, Essen, Liverpool, and Marseille), conventional field-based TV has been translated into image-guided high-precision craniospinal TV by a group of expert paediatric radiation oncologists and enhanced by MRI images of liquor distribution. RESULTS The CTVcranial should include the whole brain, cribriform plate, most inferior part of the temporal lobes, and the pituitary fossa. If the full length of both optic nerves is not included, the dose received by different volumes of optic nerve should be recorded to correlate with future patterns of relapse (no consensus). The CTVcranial should be modified to include the dural cuffs of cranial nerves as they pass through the skull base foramina. Attempts to spare the cochlea by excluding CSF within the internal auditory canal should be avoided. The CTVspinal should include the entire subarachnoid space, including nerve roots laterally. The lower limit of the spinal CTV is at the lower limit of the thecal sac, best visible on MRI scan. There is no need to include sacral root canals in the spinal CTV. CONCLUSION This consensus guideline has the potential to improve consistency of craniospinal TV delineation in an era of high-precision radiotherapy. This proposal will be incorporated in the RTQA guidelines of future SIOPE-BTG trials using CSI.