Localized incompletely resected standard risk rhabdomyosarcoma in children and adolescents: Results from the European Paediatric Soft Tissue Sarcoma Study Group RMS 2005 trial.

BACKGROUND: The authors report the prospective evaluation of reduced dose alkylator chemotherapy combined with radiotherapy for European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) standard risk nonalveolar rhabdomyosarcoma (NA-RMS). PATIENTS AND METHODS: Localized node negative Intergroup Rhabdomyosarcoma Study (IRS) II/III NA-RMS at favorable sites (subgroup C), <25 years old, received five cycles of ifosfamide, vincristine, and dactinomycin (IVA) chemotherapy (30 g/m2 ifosfamide) and four cycles of vincristine and dactinomycin (if receiving radiotherapy), or nine cycles of IVA (54 g/m2 ifosfamide) ± radiotherapy. Delayed primary tumor excision was considered for IRS III tumors. The primary end points were event-free survival (EFS) and overall survival (OS). RESULTS: From October 2005 to December 2016, 359 evaluable patients were recruited: orbit, 164 (45.7%); head and neck nonparameningeal, 77 (21.4%); and genitourinary non-bladder/prostate, 118 (32.9%). EFS and OS were 77.4% (95% confidence interval [CI], 72.5-81.6) and 93.5% (95% CI, 90.1-95.8), respectively. Lower dose alkylator chemotherapy and radiotherapy achieved 5-year OS of 93.7% but the difference with higher dose alkylator chemotherapy +/- radiotherapy was not significant (p = 0.8003). Adjuvant radiotherapy improved EFS with 5-year estimates of 84.7% versus 65.2% for nonirradiated (p < .0001), but not OS (p = .9298). Omitting radiotherapy for orbital tumors reduced OS (5-year was 87.1% vs. 97.3% for irradiated, p = .0257). Following R0 resection (n = 60), radiotherapy did not significantly improve EFS or OS. CONCLUSIONS: Radiotherapy for local tumor control allows for reduction of cumulative dose of alkylators in EpSSG standard risk subgroup C RMS patients. The omission of radiotherapy did not affect OS in all patients except those with orbital RMS and was associated with inferior EFS.

Facial deformation following treatment for pediatric head and neck rhabdomyosarcoma; the difference between treatment modalities. Results of a trans-Atlantic, multicenter cross-sectional cohort study.

BACKGROUND: The four different local therapy strategies used for head and neck rhabdomyosarcoma (HNRMS) include proton therapy (PT), photon therapy (RT), surgery with radiotherapy (Paris-method), and surgery with brachytherapy (AMORE). Local control and survival is comparable; however, the impact of these different treatments on facial deformation is still poorly understood. This study aims to quantify facial deformation and investigates the differences in facial deformation between treatment modalities. METHODS: Across four European and North American institutions, HNRMS survivors treated between 1990 and 2017, more than 2 years post treatment, had a 3D photograph taken. Using dense surface modeling, we computed facial signatures for each survivor to show facial deformation relative to 35 age-sex-ethnicity-matched controls. Additionally, we computed individual facial asymmetry. FINDINGS: A total of 173 HNRMS survivors were included, survivors showed significantly reduced facial growth (p < .001) compared to healthy controls. Partitioned by tumor site, there was reduced facial growth in survivors with nonparameningeal primaries (p = .002), and parameningeal primaries (p ≤.001), but not for orbital primaries (p = .080) All patients were significantly more asymmetric than healthy controls, independent of treatment modality (p ≤ .001). There was significantly more facial deformation in orbital patients when comparing RT to AMORE (p = .046). In survivors with a parameningeal tumor, there was significantly less facial deformation in PT when compared to RT (p = .009) and Paris-method (p = .007). INTERPRETATION: When selecting optimal treatment, musculoskeletal facial outcomes are an expected difference between treatment options. These anticipated differences are currently based on clinicians' bias, expertise, and experience. These data supplement clinician judgment with an objective analysis highlighting the impact of patient age and tumor site between existing treatment options.

Quantitative diffusion-weighted MRI response assessment in rhabdomyosarcoma: an international retrospective study on behalf of the European paediatric Soft tissue sarcoma Study Group Imaging Committee.

OBJECTIVE: To investigate the feasibility of diffusion-weighted magnetic resonance imaging (DW-MRI) as a predictive imaging marker after neoadjuvant chemotherapy in patients with rhabdomyosarcoma. MATERIAL AND METHODS: We performed a multicenter retrospective study including pediatric, adolescent and young adult patients with rhabdomyosarcoma, Intergroup Rhabdomyosarcoma Study group III/IV, treated according to the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 or MTS2008 studies. DW-MRI was performed according to institutional protocols. We performed two-dimensional single-slice tumor delineation. Areas of necrosis or hemorrhage were delineated to be excluded in the primary analysis. Mean, median and 5th and 95th apparent diffusion coefficient (ADC) were extracted. RESULTS: Of 134 included patients, 82 had measurable tumor at diagnosis and response and DW-MRI scans of adequate quality and were included in the analysis. Technical heterogeneity in scan acquisition protocols and scanners was observed. Mean ADC at diagnosis was 1.1 (95% confidence interval [CI]: 1.1-1.2) (all ADC expressed in * 10-3 mm2/s), versus 1.6 (1.5-1.6) at response assessment. The 5th percentile ADC was 0.8 (0.7-0.9) at diagnosis and 1.1 (1.0-1.2) at response. Absolute change in mean ADC after neoadjuvant chemotherapy was 0.4 (0.3-0.5). Exploratory analyses for association between ADC and clinical parameters showed a significant difference in mean ADC at diagnosis for alveolar versus embryonal histology. Landmark analysis at nine weeks after the date of diagnosis showed no significant association (hazard ratio 1.3 [0.6-3.2]) between the mean ADC change and event-free survival. CONCLUSION: A significant change in the 5th percentile and the mean ADC after chemotherapy was observed. Strong heterogeneity was identified in DW-MRI acquisition protocols between centers and in individual patients.

Local control of parameningeal rhabdomyosarcoma: An expert consensus guideline from the International Soft Tissue Sarcoma Consortium (INSTRuCT).

The International Soft Tissue Sarcoma Database Consortium (INSTRuCT) consists of a collaboration between the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, the European pediatric Soft Tissue Sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). As part of the larger initiative of INSTRuCT to provide consensus expert opinions for clinical treatment of pediatric soft tissue sarcoma, we sought to provide updated, evidenced-based consensus guidelines for local treatment of parameningeal rhabdomyosarcoma using both existing literature as well as recommendations from the relevant cooperative group clinical trials. Overall, parameningeal rhabdomyosarcoma represents a distinctly challenging disease to treat, given its location near many critical structures in the head and neck, frequently advanced local presentation, and predilection for local failure. Definitive chemoradiation remains the standard treatment approach for parameningeal rhabdomyosarcoma, with surgery often limited to biopsy or salvage therapy for recurrent disease. In this consensus paper, we specifically discuss consensus guidelines and evidence for definitive local management with radiotherapy, with a focus on imaging for radiotherapy planning, dose and timing of radiation, approach for nodal irradiation, various radiation techniques, including proton therapy, and the limited role of surgical resection.

Perianal/perineal rhabdomyosarcoma: Results of the SIOP MMT 95, Italian RMS 96, and EpSSG RMS 2005 studies.

BACKGROUND/OBJECTIVES: Rhabdomyosarcoma of the perianal/perineal region (PRMS) is rare, with poor survival and limited understanding of the functional consequences of treatment. DESIGN/METHODS: International Society of Pediatric Oncology (SIOP) malignant mesenchymal tumor (MMT) 95, Italian RMS 96, and European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS 2005 studies were interrogated to identify factors that impact survival; in RMS 2005, functional outcomes were analyzed. RESULTS: Fifty patients (nonmetastatic) were identified, median age 6.4 years (range: 0.1-19.6): 29 male, 21 female. Tumors were >5 cm in 33 patients. Histopathological subtype was alveolar in 35. Lymph nodes were involved in 23 patients. In RMS 2005, 16/21 (76%) tested alveolar tumors had positive FOXO1 fusion status. Diagnostic biopsy was performed in 37. Primary resection (13) was complete (R0) in one. Delayed primary excision (16) was complete in three. Radiotherapy (RT) in 34/50 patients included external beam (28), brachytherapy (3), and both (3). Nodal RT was given in 16/23 N1 patients (70%). Median follow-up of alive patients (29) was 84.1 months (range: 3.6-221.1). Relapse or progression occurred in 24 patients (48%), 87% were fatal and most events (63%) were locoregional. Five-year event-free survival (EFS) was 47.8 (95% CI: 32.8-61.3), and 5-year overall survival (OS) was 52.6 (95% CI: 36.7-66.2), with age ≥10 years and tumor size >5 cm impacting 5-year EFS and OS (p < .05). Functional outcome data showed bowel, genito-urinary, and psychological issues; fecal incontinence in four of 21 survivors, and urinary symptoms in two of 21. CONCLUSIONS: About 60% of patients with nonmetastatic PRMS survive; older patients and those with large tumors have the worst outcomes. Biopsy should be the initial procedure, and definitive local therapy individualized. Quality-of-life and functional studies are needed to better understand the consequences of treatment.

Non-rhabdomyosarcoma soft-tissue sarcoma.

Non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS) comprise 4% of childhood cancers and consist of numerous histologic subtypes. Prognostic factors associated with poor outcome include high histologic grade, large tumor size, presence of metastases, and unresectability. Complete surgical resection is critical for the best oncologic outcomes and is prioritized in treatment algorithms. The use of radiation therapy (RT) and chemotherapy is based upon factors such as resectability, histologic grade, tumor size, and stage. North American and European trials are defining a risk-based approach to NRSTS to limit treatment-related toxicity and to maximize therapeutic efficacy. In this paper, we summarize the current roles of surgery, RT, and chemotherapy in NRSTS and describe ongoing research that is advancing the care of NRSTS patients.

Rhabdomyosarcoma.

Rhabdomyosarcoma is a heterogeneous disease both in presentation and histology. Improvements in a multimodality therapy resulted in the improved overall survival for patients with a low-risk and intermediate-risk disease but not for patients with a metastatic disease. We reviewed and contrasted the North American and European practice patterns, though ultimately the principles of staging, surgery, radiation therapy, and chemotherapy are similar in both Children's Oncology Group and International Society of Paediatric Oncology treatment approaches. Efforts are underway to investigate improved local control rates in higher risk patients using radiation dose escalation strategies, and delayed primary excision in select cases. The prognostic significance of imaging-based chemotherapy response, proton therapy, novel biomarkers, and targeted drugs will be determined in upcoming clinical trials.

Quality assurance in radiation oncology.

The Children's Oncology Group (COG) has a strong quality assurance (QA) program managed by the Imaging and Radiation Oncology Core (IROC). This program consists of credentialing centers and providing real-time management of each case for protocol compliant target definition and radiation delivery. In the International Society of Pediatric Oncology (SIOP), the lack of an available, reliable online data platform has been a challenge and the European Society for Paediatric Oncology (SIOPE) quality and excellence in radiotherapy and imaging for children and adolescents with cancer across Europe in clinical trials (QUARTET) program currently provides QA review for prospective clinical trials. The COG and SIOP are fully committed to a QA program that ensures uniform execution of protocol treatments and provides validity of the clinical data used for analysis.

Alveolar rhabdomyosarcoma with regional nodal involvement: Results of a combined analysis from two cooperative groups.

BACKGROUND: Treatment of children and adolescents with alveolar rhabdomyosarcoma (ARMS) and regional nodal involvement (N1) have been approached differently by North American and European cooperative groups. In order to define a better therapeutic strategy, we analyzed two studies conducted between 2005 and 2016 by the European paediatric Soft tissue sarcoma Study Group (EpSSG) and Children's Oncology Group (COG). METHODS: We retrospectively identified patients with ARMS N1 enrolled in either EpSSG RMS2005 or in COG ARST0531. Chemotherapy in RMS2005 comprised ifosfamide + vincristine + dactinomycin + doxorubicin (IVADo), IVA and maintenance (vinorelbine, cyclophosphamide); in ARST0531, it consisted of either vincristine + dactinomycin + cyclophosphamide (VAC) or VAC alternating with vincristine + irinotecan (VI). Local treatment was similar in both protocols. RESULTS: The analysis of the clinical characteristics of 239 patients showed some differences between study groups: in RMS2005, advanced Intergroup Rhabdomyosarcoma Study Group (IRS) and large tumors predominated. There were no differences in outcomes between the two groups: 5-year event-free survival (EFS), 49% (95% confidence interval [CI]: 39-59) and 44% (95% CI: 30-58), and overall survival (OS), 51% (95% CI: 41-61) and 53.6% (95% CI: 40-68) in RMS2005 and ARST0531, respectively. In RMS2005, EFS of patients with FOXO1-positive tumors was significantly inferior to those with FOXO1-negative (49.3% vs 73%, P = .034). In contrast, in ARST0531, EFS of patients with FOXO1-positive tumors was 45% compared with 43.8% for those with FOXO1-negative. CONCLUSIONS: The outcome of patients with ARMS N1 was similar in both protocols. However, patients with FOXO1 fusion-negative tumors enrolled in RMS2005 showed a significantly better outcome, suggesting that different strategies of chemotherapy may have an impact in the outcome of this subgroup of patients.

High grade gliomas in young children: The South Thames Neuro-Oncology unit experience and recent advances in molecular biology and targeted therapies.

High grade gliomas (HGG) have a dismal prognosis with survival rates of 15-35%. Approximately 10-12% of pediatric HGG occur in young children and their molecular biology and clinical outcomes differ from those arising at older ages. We report on four children aged <5 years newly diagnosed with non-brainstem HGG between 2011 and 2018 who were treated with surgery and BBSFOP chemotherapy. Two died of tumor progression. The other two are still alive without radiotherapy at 3.8 and 3.9 years from diagnosis: one of whom remains disease-free off treatment; and the other one, whose tumor harbored a KCTD16:NTRK2 fusion, went on to receive larotrectinib. Additionally we review the general management, outcomes and latest updates in molecular biology and targeted therapies for young children with HGG. Infant gliomas can be stratified in molecular subgroups with clinically actionable oncogenic drivers. Chemotherapy-based strategies can avoid or delay the need for radiotherapy in young children with HGG. Harnessing the potential of NTRK, ALK, ROS1 and MET inhibitors offers the opportunity to optimize the therapeutic armamentarium to improve current outcomes for these children.

Radiological pseudoprogression post-radiotherapy in a child with pineal germ cell tumour.

Little is known about pseudoprogression in brain tumours other than gliomas. A 9-year-old male child with a pineal teratoma/germinoma underwent surgical resection followed by adjuvant chemo-radiotherapy. The magnetic resonance imaging scan 4 months post-radiotherapy showed a contrast-enhancing lesion within the surgical cavity suspicious of recurrence. These radiological findings subsequently resolved without any specific intervention. The child continues in remission 2 years post-treatment. This case illustrates the occurrence of pseudoprogression post-radiotherapy in intracranial GCT and highlights an unmet need for greater implementation of functional imaging techniques in paediatric neuro-oncology to avoid undue discontinuation of effective treatments or inappropriate enrolment in clinical trials.

Management of vertebral radiotherapy dose in paediatric patients with cancer: consensus recommendations from the SIOPE radiotherapy working group.

Inhomogeneities in radiotherapy dose distributions covering the vertebrae in children can produce long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia. In the published literature, many often interrelated variables have been reported to affect the extent of potential radiotherapy damage to the spine. Articles published in the 2D and 3D radiotherapy era instructed radiation oncologists to avoid dose inhomogeneity over growing vertebrae. However, in the present era of highly conformal radiotherapy, steep dose gradients over at-risk structures can be generated and thus less harm is caused to patients. In this report, paediatric radiation oncologists from leading centres in 11 European countries have produced recommendations on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimise the risk of long-term spinal problems. Based on available information, it is advised that homogeneous vertebral radiotherapy doses should be delivered in children who have not yet finished the pubertal growth spurt. If dose fall-off within vertebrae cannot be avoided, acceptable dose gradients for different age groups are detailed here. Vertebral delineation should include all primary ossification centres and growth plates, and therefore include at least the vertebral body and arch. For partial spinal radiotherapy, the number of irradiated vertebrae should be restricted as much as achievable, particularly at the thoracic level in young children (<6 years old). There is a need for multicentre research on vertebral radiotherapy dose distributions for children, but until more valid data become available, these recommendations can provide a basis for daily practice for radiation oncologists who have patients that require vertebral radiotherapy.

Managing peritoneal involvement in children and young people with rhabdomyosarcoma: A single-center experience from the United Kingdom.

We describe our experience in managing nine children and adolescents with rhabdomyosarcoma (RMS) and peritoneal involvement. The radiological pattern of peritoneal involvement was diverse from only ascites to solid peritoneal mass/omental caking. Treatment included systemic chemotherapy in all, surgery in three, and radiotherapy in eight. Two patients with presumed nonmalignant ascites, no solid peritoneal metastasis, nonalveolar histology, near-complete resection of residual disease, and radiotherapy survived long term. One patient has just completed treatment, and the remaining six relapsed/progressed at the time of reporting. Five of six patients died after a median of 5 (3-7) months from relapse despite second-line chemotherapy.

Psychosocial well-being of long-term survivors of pediatric head-neck rhabdomyosarcoma.

BACKGROUND: Head and neck rhabdomyosarcoma (HNRMS) survivors are at risk to develop adverse events (AEs). The impact of these AEs on psychosocial well-being is unclear. We aimed to assess psychosocial well-being of HNRMS survivors and examine whether psychosocial outcomes were associated with burden of therapy. PROCEDURE: Sixty-five HNRMS survivors (median follow-up: 11.5 years), treated in the Netherlands and the United Kingdom between 1990 and 2010 and alive ≥2 years after treatment visited the outpatient multidisciplinary follow-up clinic once, in which AEs were scored based on a predefined list according to the Common Terminology Criteria for Adverse Events. Survivors were asked to complete questionnaires on health-related quality of life (HRQoL; PedsQL and YQOL-FD), self-perception (KIDSCREEN), and satisfaction with appearances (SWA). HRQoL and self-perception scores were compared with reference values, and the correlation between physician-assessed AEs and psychosocial well-being was assessed. RESULTS: HNRMS survivors showed significantly lower scores on PedsQL school/work domain (P ≤ 0.01, P = 0.02, respectively), YQOL-FD domains negative self-image and positive consequences (P ≤ 0.01, P = 0.04, respectively) compared with norm data; scores on negative consequences domain were significantly higher (P = 0.03). Over 50% of survivors negatively rated their appearances on three or more items. Burden of AEs was not associated with generic HRQoL and self-perception scores, but was associated with disease-specific QoL (YQOL-FD). CONCLUSION: In general, HRQoL in HNRMS survivors was comparable to reference groups; however, survivors did report disease-specific consequences. We therefore recommend including specific questionnaires related to difficulties with facial appearance in a systematic monitoring program to determine the necessity for tailored care.

Post-radiotherapy apparent diffusion coefficient (ADC) in children and young adults with high-grade gliomas and diffuse intrinsic pontine gliomas.

Objectives: Diffusion-weighted magnetic resonance imaging (DW-MRI) offers potential to monitor response and predict survival in high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). We hypothesized that post-radiotherapy DW-MRI may provide prognostic imaging biomarkers in children and young adults with these tumors. Methods: Patients aged ≤21 years diagnosed between 2005 and 2012 were eligible. The tumor median apparent diffusion coefficient (ADC) and its 5th percentile (C5-ADC) were determined at the first post-radiotherapy scan and at the time of radiological progression. DW-MRI parameters were correlated with survival endpoints, temozolomide use and pseudoprogression, when it occurred. Results: Out of 40 patients (20 HGG, 20 DIPG), 23 had evaluable DW-MRI post-radiotherapy and 25 at radiological progression. There were 6 episodes of pseudoprogression. Hazard ratios (95%CI) for progression-free survival were 0.998 (0.993-1.003) for median ADC and 1.003 (0.996-1.010) for C5-ADC. Hazard ratios (95%CI) for overall survival were 1.0009 (0.996-1.006) for median ADC and 0.998 (0.992-1.004) for C5-ADC. Post-radiotherapy median and C5-ADC values were not significantly different between patients treated with radiotherapy alone versus radiotherapy/temozolomide. The median and C5-ADC values were not significantly different at the time of pseudoprogression compared to those at tumor progression. Conclusions: Post-radiotherapy median ADC and C5-ADC were not prognostic, nor able to differentiate radiosensitization with temozolomide or occurrence of pseudoprogression in this cohort of HGG and DIPG patients. Further exploration of alternative DW parameters, study timepoints or data modeling may contribute to the development of prognostic/predictive imaging biomarkers for children and young adults with HGG or DIPG.

Fusion status in patients with lymph node-positive (N1) alveolar rhabdomyosarcoma is a powerful predictor of prognosis: Experience of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).

BACKGROUND: Alveolar rhabdomyosarcoma (aRMS) with lymph node involvement (N1 classification) accounts for up to 10% of all cases of RMS. The prognosis is poor, and is comparable to that of distant metastatic disease. In the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS2005 protocol, patients with a histologic diagnosis of aRMS/N1 received intensified chemotherapy with systematic locoregional treatment. METHODS: Patients with aRMS/N1 were enrolled prospectively after primary surgery/biopsy and fusion status was assessed in tumor samples. All patients received 9 cycles of induction chemotherapy and 6 months of maintenance therapy. Local treatment included radiotherapy to the primary site and lymph nodes with or without secondary surgical resection. RESULTS: A total of 103 patients were enrolled. The clinical characteristics of the patients were predominantly unfavorable: 90% had macroscopic residual disease after initial surgery/biopsy, 63% had locally invasive tumors, 77% had a tumor measuring >5 cm, and 81% had disease at unfavorable sites. Fusion genes involving forkhead box protein O1 (FOXO1) were detected in 56 of 84 patients. Events occurred in 52 patients: 43 developed disease recurrence, 7 had disease that was refractory to treatment, and 2 patients developed second neoplasms. On univariate analysis, unfavorable disease site, tumor invasiveness, Intergroup Rhabdomyosarcoma Study group III, and fusion-positive status correlated with worse prognosis. The 5-year event-free survival rate of patients with fusion-positive tumors was 43% compared with 74% in patients with fusion-negative tumors (P = .01). On multivariate analysis, fusion positivity and tumor invasiveness proved to be unfavorable prognostic markers. CONCLUSIONS: Fusion status and tumor invasiveness appear to have a strong impact on prognosis in patients with aRMS/N1. Fusion status will be used to stratify these patients in the next EpSSG RMS study, and treatment will be intensified in patients with fusion-positive tumors. Cancer 2018. © 2018 American Cancer Society.

Craniospinal irradiation with concomitant and adjuvant temozolomide--a feasibility assessment of toxicity in patients with glioblastoma with a PNET component.

There is no standard treatment for glioblastoma with elements of PNET (GBM-PNET). Conventional treatment for glioblastoma is surgery followed by focal radiotherapy with concurrent temozolomide. Given the increased propensity for neuroaxial metastases seen with GBM-PNETs, craniospinal irradiation (CSI) with temozolomide (TMZ) could be a feasible treatment option but little is known regarding its toxicity. The clinical records of all patients treated at two UK neuro-oncology centres with concurrent CSI and TMZ were examined for details of surgery, radiotherapy, chemotherapy and toxicities related to the CSI-TMZ component of their treatment. Eight patients were treated with CSI-TMZ, the majority (6/8) for GBM-PNET. All patients completed radiotherapy to the craniospinal axis 35-40 Gy in 20-24 daily fractions with a focal boost to the tumour of 14-23.4 Gy in 8-13 daily fractions. Concurrent TMZ was administered at 75 mg/m(2) for seven of the cohort, with the other patient receiving 50 mg/m(2). The most commonly observed non-haematological toxicities were nausea and vomiting, with all patients experiencing at least grade 2 symptoms of either or both. All patients had at least grade 3 lymphopaenia. Two patients experience grade 4 neutropaenia and grade 3 thrombocytopaenia. Three of the eight patients required omission of TMZ for part of their chemoradiotherapy and 3/8 required hospital admission at some point during chemoradiotherapy. The addition of TMZ to CSI did not interrupt radiotherapy. Principal toxicities were neutropaenia, lymphopaenia, thrombocytopaenia, nausea and vomiting. Treatment with CSI-TMZ merits further investigation and may be suitable for patients with tumours at high-risk of metastatic spread throughout the CNS who have TMZ-sensitive pathologies.