Gail Horan

Highlights from the Third International Central Nervous System Germ Cell Tumour symposium: laying the foundations for future consensus.

The Third International Central Nervous System (CNS) Germ Cell Tumour (GCT) Symposium brought together over 100 delegates from all over the world to learn about the latest developments in these tumours and discuss future strategies for their management. Some areas of consensus were agreed upon, and controversies were discussed. Among these, the classification of GCTs and the surgical approach to their management were among the greatest areas of difference between different parts of the world. The need for radiotherapy (RT) as a part of standard first-line management for all malignant CNS GCTs was agreed, as well as the need for additional chemotherapy to maximise the cure in nongerminomatous malignant GCTs; the benefit of the addition of chemotherapy in localised germinoma to reduce the RT burden was also accepted as a good practice. The potential of biological parameters to assist the future diagnosis, treatment stratification, and disease monitoring for CNS GCTs was discussed. Such biological parameters may also represent targets for the development of novel therapies. The need for further collaboration between groups engaged in biological studies was agreed. The merits of proton beam RT were debated, and the importance of mitigating the long-term side effects of the treatment was underlined by a session on late effects.

Non‐pineal supratentorial primitive neuro‐ectodermal tumors (sPNET) in teenagers and young adults: Time to reconsider cisplatin based chemotherapy after cranio‐spinal irradiation?

Supratentorial PNET (sPNET) are rare CNS tumors of embryonal origin arising in children and adults. The treatment of sPNET for all age groups at our cancer center has been based on the management of medulloblastoma (MB), involving neurosurgical debulking followed by cranio‐spinal irradiation (CSI) and systemic chemotherapy.

Trabectedin for advanced soft tissue sarcomas: a single institution experience

BACKGROUND We retrospectively analyzed data from patients who had been treated with trabectedin at our institution between April 2009 and August 2011. PATIENTS & METHODS Data from 25 patients with recurrent soft tissue sarcoma (leiomyosarcoma: n = 8; liposarcoma: n = 5) were used to assess the efficacy and safety of trabectedin 1.5 mg/m(2) given every 3 weeks. RESULTS Most patients (n = 14) had been heavily pretreated with ≥ 2 previous chemotherapy lines. Eight (32%) patients achieved a partial response according to dimensional and tumor density changes, and seven (28%) patients had stable disease for ≥ 3 months (clinical benefit rate = 60%; n = 15). Median progression-free survival was 6.4 months and overall survival 19.3 months. Common adverse events were fatigue, nausea, anemia and transient transaminase increases. CONCLUSION Treatment with trabectedin is effective and well tolerated in heavily pretreated soft tissue sarcoma patients. Tapering dexamethasone courses and switching trabectedin administration to an every 4 weeks schedule effectively dealt with persistent fatigue without compromising effectiveness.

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.

Prevention of radiotherapy-induced neurocognitive dysfunction in survivors of paediatric brain tumours: the potential role of modern imaging and radiotherapy techniques

Neurocognitive dysfunction is the leading cause of reduced quality of life in long-term survivors of paediatric brain tumours. Radiotherapy is one of the main contributors to neurocognitive sequelae. Current approaches for prevention and reduction of neurocognitive dysfunction include avoidance of radiotherapy in young children and reduction of the radiotherapy dose and volume of brain irradiated. Substantial advances have been made in brain imaging, especially with functional imaging and fibre tracking with the use of diffusion tensor imaging. Radiotherapy techniques for photon therapy have also evolved, with widespread use of techniques such as image-guided radiotherapy, volumetric modulated arc therapy, helical tomotherapy, and adaptive radiotherapy. The number of proton beam and heavy ion therapy facilities is increasing worldwide and there is great enthusiasm for clinical use of advanced MRI-guided radiotherapy systems. Here, we review the potential role of modern imaging and innovative radiotherapy techniques in minimisation of neurocognitive sequelae in children with brain tumours, and discuss various strategies to integrate these advances to drive further research.

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.

Uncommon low-grade brain tumors

The 2016 World Health Organization (WHO) classification of primary central nervous system (CNS) tumors includes numerous uncommon (representing ≤1% of tumors) low-grade (grades I-II) brain neoplasms with varying clinical behaviors and outcomes. Generally, gross tumor or maximal safe resection is the primary treatment. Adjuvant treatments, though their exact role is unknown, may be considered individually based on pathological subtypes and a proper assessment of risks and benefits. Targetable mutations such as BRAF (proto-oncogene B-Raf), TRAIL (tumor necrosis factor apoptosis inducing ligand), and PDGFR (platelet derived growth factor receptor) have promising roles in future management.

A Comprehensive Single Institutional Review of 2 Years in a Designated Fast-Track Sarcoma Diagnostic Clinic Linked with a Sarcoma Specialist Advisory Group: Meeting the Target but Failing the Task?

Background. National guidelines prompted the implementation of a designated two-week wait referral pathway to facilitate the early diagnosis of sarcomas, to improve treatment outcomes. Methods. Patients referred to the Cambridge Sarcoma Diagnostic Clinic between January 2013 and December 2014 were identified through the electronic appointments system. Information was retrospectively retrieved about patient characteristics and details of the diagnostic pathway. Results. 17.3% of patients referred (69/397) were diagnosed with a malignancy. Of these, 59.3% (41/69) had primary sarcomas, 17.4% (12/69) had metastatic cancer, and 23.2% (16/69) had a different primary malignancy. 15% of the 41 sarcomas were <5 cm, 34% in the 5–10 cm range, and 51% >10 cm. Sarcomas diagnosed through this clinic represented 13% (41/315) of sarcomas managed at the centre during the same 2 years. Conclusion. While we achieved the target of 10% (41/397) sarcoma diagnosis rate in the rapid access clinic, only 15% of these were <5 cm better prognosis lesions. This calls into question the “real world” impact of such diagnostic clinics on early diagnosis of sarcomas. In order to enhance generic cancer diagnostic skills, training in these diagnostic clinics could be usefully integrated into national training curricula for both surgical and nonsurgical oncologists.