Second surgery for progressive glioblastoma: a multi-centre questionnaire and cohort-based review of clinical decision-making and patient outcomes in current practice.

PURPOSE: Glioblastoma prognosis is poor. Treatment options are limited at progression. Surgery may benefit, but no quality guidelines exist to inform patient selection. We sought to describe variations in surgical management at progression, highlight where further evidence is needed, and build towards a consensus strategy. METHODS: Current practice in selection of patients with progressive GBM for second surgery was surveyed online amongst specialists in the UK and Europe. We complemented this with an assessment of practice in a retrospective cohort study from six United Kingdom neurosurgical units. We used descriptive statistics to analyse the data. RESULTS: 234 questionnaire responses were received. Maintaining or improving patient quality of life was key to decision making, with variation as to whether patient age, performance status or intended extent of resection was relevant. MGMT methylation status was not important. Half considered no minimum time after first surgery. 288 patients were reported in the cohort analysis. Median time to second surgery from first surgery 390 days. Median overall survival 815 days, with no association between time to second surgery and time to death (p = 0.874). CONCLUSIONS: This is the most wide-ranging examination of contemporaneous practice in management of GBM progression. Without evidence-based guidelines, the variation is unsurprising. We propose consensus guidelines for consideration, to reduce heterogeneity in decision making, support data collection and analysis of factors influencing outcomes, and to inform clinical trials to establish whether second surgery improves patient outcomes, or simply selects to patients already performing well.

Tumour Volume and Dose Influence Outcome after Surgery and High-dose Photon Radiotherapy for Chordoma and Chondrosarcoma of the Skull Base and Spine.

AIMS: To evaluate the long-term outcomes of patients with chordoma and low-grade chondrosarcoma after surgery and high-dose radiotherapy. MATERIALS AND METHODS: High-dose photon radiotherapy was delivered to 28 patients at the Neuro-oncology Unit at Addenbrooke's Hospital (Cambridge, UK) between 1996 and 2016. Twenty-four patients were treated with curative intent, 17 with chordoma, seven with low-grade chondrosarcoma, with a median dose of 65 Gy (range 65-70 Gy). Local control and survival rates were calculated using the Kaplan-Meier method. RESULTS: The median follow-up was 83 months (range 7-205 months). The 5 year disease-specific survival for chordoma patients treated with radical intent was 85%; the local control rate was 74%. The 5 year disease-specific survival for chondrosarcoma patients treated with radical intent was 100%; the local control rate was 83%. The mean planning target volume (PTV) was 274.6 ml (median 124.7 ml). A PTV of 110 ml or less was a good predictor of local control, with 100% sensitivity and 63% specificity. For patients treated with radical intent, this threshold of 110 ml or less for the PTV revealed a statistically significant difference when comparing local control with disease recurrence (P = 0.019, Fisher's exact test). Our data also suggest that the probability of disease control may be partly related to both target volume and radiotherapy dose. CONCLUSION: Our results show that refined high-dose photon radiotherapy, following tumour resection by a specialist surgical team, is effective in the long-term control of chordoma and low-grade chondrosarcoma, even in the presence of metal reconstruction. The results presented here will provide a useful source for comparison between high-dose photon therapy and proton beam therapy in a UK setting, in order to establish best practice for the management of chordoma and low-grade chondrosarcoma.

Automatic contour propagation using deformable image registration to determine delivered dose to spinal cord in head-and-neck cancer radiotherapy.

To determine delivered dose to the spinal cord, a technique has been developed to propagate manual contours from kilovoltage computed-tomography (kVCT) scans for treatment planning to megavoltage computed-tomography (MVCT) guidance scans. The technique uses the Elastix software to perform intensity-based deformable image registration of each kVCT scan to the associated MVCT scans. The registration transform is then applied to contours of the spinal cord drawn manually on the kVCT scan, to obtain contour positions on the MVCT scans. Different registration strategies have been investigated, with performance evaluated by comparing the resulting auto-contours with manual contours, drawn by oncologists. The comparison metrics include the conformity index (CI), and the distance between centres (DBC). With optimised registration, auto-contours generally agree well with manual contours. Considering all 30 MVCT scans for each of three patients, the median CI is [Formula: see text], and the median DBC is ([Formula: see text]) mm. An intra-observer comparison for the same scans gives a median CI of [Formula: see text] and a DBC of ([Formula: see text]) mm. Good levels of conformity are also obtained when auto-contours are compared with manual contours from one observer for a single MVCT scan for each of 30 patients, and when they are compared with manual contours from six observers for two MVCT scans for each of three patients. Using the auto-contours to estimate organ position at treatment time, a preliminary study of 33 patients who underwent radiotherapy for head-and-neck cancers indicates good agreement between planned and delivered dose to the spinal cord.

Highly Conformal Craniospinal Radiotherapy Techniques Can Underdose the Cranial Clinical Target Volume if Leptomeningeal Extension through Skull Base Exit Foramina is not Contoured.

AIMS: Craniospinal irradiation (CSI) remains a crucial treatment for patients with medulloblastoma. There is uncertainty about how to manage meningeal surfaces and cerebrospinal fluid (CSF) that follows cranial nerves exiting skull base foramina. The purpose of this study was to assess plan quality and dose coverage of posterior cranial fossa foramina with both photon and proton therapy. MATERIALS AND METHODS: We analysed the radiotherapy plans of seven patients treated with CSI for medulloblastoma and primitive neuro-ectodermal tumours and three with ependymoma (total n = 10). Four had been treated with a field-based technique and six with TomoTherapy™. The internal acoustic meatus (IAM), jugular foramen (JF) and hypoglossal canal (HC) were contoured and added to the original treatment clinical target volume (Plan_CTV) to create a Test_CTV. This was grown to a test planning target volume (Test_PTV) for comparison with a Plan_PTV. Using Plan_CTV and Plan_PTV, proton plans were generated for all 10 cases. The following dosimetry data were recorded: conformity (dice similarity coefficient) and homogeneity index (D2 - D98/D50) as well as median and maximum dose (D2%) to Plan_PTV, V95% and minimum dose (D99.9%) to Plan_CTV and Test_CTV and Plan_PTV and Test_PTV, V95% and minimum dose (D98%) to foramina PTVs. RESULTS: Proton and TomoTherapy™ plans were more conformal (0.87, 0.86) and homogeneous (0.07, 0.04) than field-photon plans (0.79, 0.17). However, field-photon plans covered the IAM, JF and HC PTVs better than proton plans (P = 0.002, 0.004, 0.003, respectively). TomoTherapy™ plans covered the IAM and JF better than proton plans (P = 0.000, 0.002, respectively) but the result for the HC was not significant. Adding foramen CTVs/PTVs made no difference for field plans. The mean Dmin dropped 3.4% from Plan_PTV to Test_PTV for TomoTherapy™ (not significant) and 14.8% for protons (P = 0.001). CONCLUSIONS: Highly conformal CSI techniques may underdose meninges and CSF in the dural reflections of posterior fossa cranial nerves unless these structures are specifically included in the CTV.

Clinical and practical considerations for the use of intensity-modulated radiotherapy and image guidance in neuro-oncology.

Intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy offer significant opportunities to improve outcomes for our patients, although they are not yet as widely used as they might be. IMRT allows better target coverage and lower organ at risk doses than conformal therapy. It also allows inhomogeneous dose plans to be developed, where these can provide benefit, either to dose escalate the tumour or reduce dose to adjacent or overlapping organs at risk. Image guidance adds precision and the possibility of careful reduction in planning target volume margins. The technologies can be valuable both for patients with highly malignant tumours, such as glioblastoma, and those with less malignant or benign tumours. In glioblastoma, temozolomide chemotherapy and surgical developments have improved survival, and developments in radiotherapy techniques should also be used to optimise outcome. Target volume delineation, including calculation of the planning target volume margin is critical. Clear definitions of the gross tumour and clinical target volumes are essential, following established guidelines. Normal tissue volume delineation is also essential for IMRT. The planning organ at risk volume has become a valuable tool to manipulate dose away from organs at risk to avoid toxicities. This is distinct from 'optimising volumes' used to drive the computer optimiser during planning. Hard data on central nervous system (CNS) normal tissue tolerance is surprisingly slight, reflecting the clinical imperative to avoid serious complications in neurological tissues. The effect of chemotherapy on radiotherapy tolerance in the CNS remains obscure, and more needs to be done to develop the knowledge base. IMRT provides better conformation of the high dose treatment to the shape of the target, and reduces the dose to normal tissue structures. Image guidance improves the accuracy of dose delivery, which is particularly important where steep dose gradients are present. These technologies should be regarded as the state-of-the-art for our CNS patients.

The value of image-guided intensity-modulated radiotherapy in challenging clinical settings.

OBJECTIVE: To illustrate the wider potential scope of image-guided intensity-modulated radiotherapy (IG-IMRT), outside of the "standard" indications for IMRT. METHODS: Nine challenging clinical cases were selected. All were treated with radical intent, although it was accepted that in several of the cases the probability of cure was low. IMRT alone was not adequate owing to the close proximity of the target to organs at risk, the risk of geographical miss, or the need to tighten planning margins, making image-guided radiotherapy an essential integral part of the treatment. Discrepancies between the initial planning scan and the daily on-treatment megavoltage CT were recorded for each case. The three-dimensional displacement was compared with the margin used to create the planning target volume (PTV). RESULTS: All but one patient achieved local control. Three patients developed metastatic disease but benefited from good local palliation; two have since died. A further patient died of an unrelated condition. Four patients are alive and well. Toxicity was low in all cases. Without daily image guidance, the PTV margin would have been insufficient to ensure complete coverage in 49% of fractions. It was inadequate by >3 mm in 19% of fractions, and by >5 mm in 9%. CONCLUSION: IG-IMRT ensures accurate dose delivery to treat the target and avoid critical structures, acting as daily quality assurance for the delivery of complex IMRT plans. These patients could not have been adequately treated without image guidance. ADVANCES IN KNOWLEDGE: IG-IMRT can offer improved outcomes in less common clinical situations, where conventional techniques would provide suboptimal treatment.

Temozolomide responsiveness in aggressive corticotroph tumours: a case report and review of the literature.

Pituitary carcinoma occurs in ~0.2% of resected pituitary tumours and carries a poor prognosis (mean survival <4 years), with standard chemotherapy regimens showing limited efficacy. Recent evidence suggests that temozolomide (TMZ), an orally-active alkylating agent used principally in the management of glioblastoma, may also be effective in controlling aggressive/invasive pituitary adenomas/carcinomas. A low level of expression of the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) predicts TMZ responsiveness in glioblastomas, and a similar correlation has been observed in the majority of aggressive pituitary adenomas/carcinomas reported to date. Here, we report a case of a silent pituitary corticotroph adenoma, which subsequently re-presented with Cushing's syndrome due to functioning hepatic metastases. The tumour exhibited low immunohistochemical MGMT expression in both primary (pituitary) and secondary (hepatic) lesions. Initial TMZ therapy (200 mg/m² for 5 days every 28 days-seven cycles) resulted in marked clinical, biochemical [>50% fall in adrenocorticotrophic hormone (ACTH)] and radiological [partial RECIST (response evaluation criteria in solid tumors) response] improvements. The patient then underwent bilateral adrenalectomy. However, despite reintroduction of TMZ therapy (further eight cycles) ACTH levels plateaued and no further radiological regression was observed. We review the existing literature reporting TMZ efficacy in pituitary corticotroph tumours, and highlight the pointers/lessons for treating aggressive pituitary neoplasia that can be drawn from experience of susceptibility and evolving resistance to TMZ therapy in glioblastoma. Possible strategies for mitigating resistance developing during TMZ treatment of pituitary adenomas/carcinomas are also considered.

Implementation of neuro-oncology service reconfiguration in accordance with NICE guidance provides enhanced clinical care for patients with glioblastoma multiforme.

BACKGROUND: Brain tumours account for <2% of all primary neoplasms but are responsible for 7% of the years of life lost from cancer before age 70 years. The latest survival trends for patients with CNS malignancies have remained largely static. The objective of this study was to evaluate the change in practice as a result of implementing the Improving Outcomes Guidance from the UK National Institute for Health and Clinical Excellence (NICE). METHODS: Patients were identified from the local cancer registry and hospital databases. We compared time from diagnosis to treatment, proportion of patients discussed at multidisciplinary team (MDT) meetings, treatment received, length of inpatient stay and survival. Inpatient and imaging costs were also estimated. RESULTS: Service reconfiguration and implementation of NICE guidance resulted in significantly more patients being discussed by the MDT--increased from 66 to 87%, reduced emergency admission in favour of elective surgery, reduced median hospital stay from 8 to 4.5 days, increased use of post-operative MRI from 17 to 91% facilitating early discharge and treatment planning, and reduced cost of inpatient stay from £2096 in 2006 to £1316 in 2009. Patients treated with optimal surgery followed by radiotherapy with concomitant and adjuvant temozolomide achieved outcomes comparable to those reported in clinical trials: median overall survival 18 months (2-year survival 35%). CONCLUSIONS: Advancing the management of neuro-oncology patients by moving from an emergency-based system of patient referral and management to a more planned elective outpatient-based pattern of care improves patient experience and has the potential to deliver better outcomes and research opportunities.

Tumour shrinkage and contour change during radiotherapy increase the dose to organs at risk but not the target volumes for head and neck cancer patients treated on the TomoTherapy HiArt™ system.

AIMS: To quantify the changes in contours of the target and organs at risk and the differences between planned and delivered doses to the target and organs at risk during the course of radiotherapy in head and neck cancer patients treated with intensity-modulated radiotherapy on the TomoTherapy HiArt™ system. MATERIALS AND METHODS: Five patients with squamous cell carcinoma of the head and neck treated with radical chemoradiotherapy using the TomoTherapy HiArt system were included in the study. The target volumes were treated to three different dose levels depending on the level of clinical risk for harbouring disease. Patient positions were assessed daily with megavoltage computed tomography (MVCT) and positional correction made before each treatment when necessary. MVCTs were superimposed on to the planning kilovoltage computed tomography images for each patient and target volumes and organ at risk volumes were re-outlined on MVCT images. Doses to clinical target volumes and organs at risk were recalculated to show the actual delivered doses. RESULTS: There was shrinkage in the volume of the parotid glands during treatment in all cases. The mean volume reduction in the ipsilateral parotid gland was more marked at 30.2%, compared with the contralateral parotid glands. However, the mean percentage dose per fraction increase was higher in the contralateral parotid glands at 24%, compared with the ipsilateral parotids. The calculated doses were higher than the planned doses in all CTV-54, CTV-60 and CTV-68, but the mean dose differences were modest, in the range 1.3-2.4%. CONCLUSIONS: We have shown that there were considerable changes in the volume and dose to the parotids during treatment. The changes in volume and dose to the clinical target volume were more modest in comparison. Adaptive radiotherapy planning can be helpful in improving the dose to the parotid glands. However, its role in the optimisation of the dosage to the clinical target volume is less likely to result in a significant clinical benefit.

Residual postoperative tumour volume predicts outcome after high-dose radiotherapy for chordoma and chondrosarcoma of the skull base and spine.

AIMS: High-dose radiotherapy after surgical debulking is the treatment of choice for chordomas and chondrosarcomas. This study reviewed our outcomes, in relation to residual tumour volume and radiation dose, in order to inform our future practice. PATIENTS AND METHODS: Nineteen patients referred to the Neuro-Oncology Unit at Addenbrooke's Hospital (Cambridge, UK) between 1996 and 2009 and treated with photon radiotherapy were reviewed. Seventeen of the 19 were treated with curative intent. The median follow-up was 53 months. The tumours in the study had a mean gross tumour volume (GTV) of 17.2 cm(3) (median 10.5 cm(3)) and a range of 0-76.3 cm(3). The median dose was 65Gy in 39 fractions. RESULTS: The 5 year cause-specific survival for radically treated patients with chordomas was 92% and the 5 year local control rate was 83%. The 5 year cause-specific survival and local control rates with chondrosarcomas were both 100%. A planning target volume (PTV) below 90 cm(3) is predictive of local control, but volumes above this are not. The GTV seems to be a better predictor of outcome: among the 17 of 19 patients treated curatively, a GTV threshold of 30 cm(3) distinguished local failures from the 15 patients with local control, with sensitivity to detect local control of 100% (95% confidence interval 78-100%), specificity 100% (95% confidence interval 16-100%) and positive predictive value 100% (95% confidence interval 78-100%). CONCLUSIONS: Our results show a high level of efficacy for fractionated photon radiotherapy after surgery, in keeping with other series. In addition, we found that although surgical debulking is essential, a small residual tumour volume may still be controlled with high-dose photon radiotherapy. This information may be relevant during neurosurgical planning, possibly allowing a reduction in risk of serious neurological deficits. This should encourage the further development of sophisticated photon radiotherapy, for patients unsuitable for proton therapy.

Excellent local control of paraganglioma in the head and neck with fractionated radiotherapy.

AIMS: Radiotherapy is an important treatment option for paraganglioma in the head and neck region. It seems to be highly effective and avoids important surgical morbidity, which can impair quality of life. The aim of this study was to evaluate the outcomes of radiotherapy for paraganglioma of the head and neck region in order to inform our future practice. MATERIALS AND METHODS: The cohort of patients for the present study comprised 21 patients who received radiotherapy between 1998 and 2008. Follow-up ranged from 6 to 132 months, median 55 months. The mean age was 48.7 years, range 20-78 years. The female:male ratio was 2 : 1. Two patients had confirmed familial tumour syndromes. The gross tumour volume in 20 cases ranged from 1.3 to 74 cm(3), mean 23.2 cm(3), median 14.7 cm(3). Five patients were treated with intensity-modulated radiotherapy. The median dose was 50 Gy in 30 fractions. RESULTS: The crude 5-year local control rate was 95% (20/21), although the 5-year actuarial local control rate was 87%. The one patient who relapsed, at 45 months after radiotherapy, had a comparatively small tumour of 10.8 cm(3). A relationship between tumour volume and local control seems unlikely. It was possible to obtain details of side-effects from electronic records for 11 patients. Grade 3 headache, which resolved, was the most serious acute side-effect. One patient had three teeth extracted due to exacerbation of dental caries, and one had deterioration of hearing thought to be due to a combination of tumour and radiotherapy. There were two serious complications in patients who had embolisation, which we no longer use. CONCLUSIONS: Our results show a high level of efficacy for fractionated external beam radiotherapy, with minimal toxicity, in keeping with other series. This should encourage the use of radiotherapy as primary treatment for paragangliomas of the head and neck region.

Skull base meningioma - comparison of intensity-modulated radiotherapy planning techniques using the moduleaf micro-multileaf collimator and helical tomotherapy.

AIMS: Therapeutic radiotherapy to lesions of the skull base is limited by complex target shapes and their proximity to organs at risk. Intensity-modulated radiotherapy (IMRT) using helical tomotherapy may result in improved dose distributions and safer dose escalation. The aim of this study was to compare plan efficacy and efficiency using, linac-based micro-multileaf collimator (mMLC) IMRT and helical tomotherapy. MATERIALS AND METHODS: Five cases of skull base meningioma, previously treated with three-dimensional conformal radiotherapy (50 Gy/30 fractions) were identified. They were re-planned to a dose of 60 Gy/30 fractions using IMRT with Moduleaf mMLC (2.5 mm) and helical tomotherapy. Plan efficacy was compared using measures of PTV(60) coverage (D(min), D(max), V(90%), V(95%) and V(100%)). Plan efficiency was assessed by comparing estimated beam-on times. RESULTS: The critical structure dose was limited to below predetermined tolerance levels in all cases, with similar doses obtained between techniques. The average PTV(60)D(max), D(min), D(med), D(mean), V(90%), V(95%) and V(100%) across the five cases achieved were as follows: mMLC IMRT: 64.9 Gy, 40.1 Gy, 60 Gy, 59.6 Gy, 95.4%, 88.8% and 69.2%, respectively; helical tomotherapy: 67.2 Gy, 50.3 Gy, 60 Gy, 59.9 Gy, 95.8%, 83.5% and 51.9%, respectively. The average treatment time per fraction was 18.4 min for IMRT with mMLC and 6.7 min for helical tomotherapy. DISCUSSION: This study shows that safe dose escalation to a dose of 60G y to skull base lesions can be achieved; using either mMLC- or helical tomotherapy-based IMRT. A plan comparison between the two solutions is difficult, but they seem to be similar in efficacy with any small differences being difficult to interpret and of questionable clinical significance. Helical tomotherapy has the advantage of a significantly decreased beam-on time.

Intensity-modulated radiotherapy plan optimisation for skull base lesions: practical class solutions for dose escalation.

AIMS: To identify practical intensity-modulated radiotherapy planning solutions when attempting dose escalation in the skull base. MATERIALS AND METHODS: Twenty cases of skull base meningioma were re-planned using a variation of beam number (three, five, seven and nine), beam arrangement (coplanar vs non-coplanar) and multileaf collimator (MLC) width (2.5 mm vs 10 mm) to 60 Gy/30 fractions. Plan quality and planning target volume coverage was assessed using planning target volume V(95%), equivalent uniform dose (EUD) and integral dose. RESULTS: Critical structures were maintained below clinical tolerance levels. The 2.5 mm MLC achieved an average improvement in V(95%) by 22.8% (P=0.0003), EUD by 3.7 Gy (P=0.002) and reduced the integral dose by 13.4 Gy (P=0.0001). V(95%) and the integral dose improved with five vs three beams and seven vs five beams, but did not change with nine vs seven beams. There was no effect of beam number on EUD. There was no difference in V(95%) (P=0.54), integral dose (P=0.44) or EUD (P=0.47) for beam arrangement used. Segments per plan increased by a factor of 1.5 with each addition of two beams to a plan, and by a factor of 2.5 for 2.5 mm MLC plans vs 10 mm MLC plans. CONCLUSIONS: We present evidence-based planning solutions for skull base intensity-modulated radiotherapy, and show that 2.5 mm MLC and five to seven beams can achieve safe dose escalation up to 60 Gy. This must be balanced with an increase in segmentation, which will increase treatment times.

Pattern of relapse after fractionated external beam radiotherapy for meningioma: experience from Addenbrooke's Hospital.

AIMS: Radiotherapy is an important treatment modality for meningioma. We aimed to review the clinical outcomes for meningioma patients treated with radiotherapy in the Addenbrooke's Hospital Oncology Department. MATERIALS AND METHODS: A retrospective chart review was carried out on patients with meningioma referred and treated in the department between 1 November 1996 and 31 October 2006. Patient details and outcomes were recorded and the results were analysed to assess survival outcomes. Survival data were confirmed by the Eastern Cancer Registration and Information Centre. RESULTS: In total, 174 patients were referred to the department for an oncology opinion. Of these, 128 proceeded to radiotherapy. The median follow-up was 5.3 years (range 2.1-11.9 years). Sixty-seven per cent of the patients were older than 50 years, and the female: male ratio was 2.2: 1. Overall survival was 78% at the time of follow-up, with death related to meningioma in 7% of the total cohort. Local control was 85% overall, 93% for grade 1 disease, 45% for grade 2 disease and 82% for grade 3 disease. Patients with non-benign disease were more likely to receive >50Gy (27% of grade 1 lesions vs 65% of grade 2/3 lesions), but despite this local control remained poor, even with the higher dose delivered (local control 60 and 40% for grade 2 lesions treated with 50 and >50Gy, respectively, and 100 and 75% for grade 3 lesions treated with 50 and >50Gy, respectively). CONCLUSIONS: Our cohort of patients had an overall local control and survival similar to those documented from other departments. Grade was an important prognostic factor. Patients treated with >50Gy had worse local control outcomes, probably due to selection bias. Dose escalation may still be appropriate for high-risk disease, and may be more effective with more conformal techniques, such as intensity-modulated radiotherapy.

An assessment of action levels in imaging strategies in head and neck cancer using TomoTherapy. Are our margins adequate in the absence of image guidance?

AIMS: To assess the effectiveness of different on-treatment correction strategies on set-up accuracy in patients with head and neck cancer (HNC) treated on a TomoTherapy HiArt system. To assess the adequacy of clinical target volume (CTV) to planning target volume (PTV) treatment planning margins when treating with intensity-modulated radiotherapy without daily image guidance. MATERIALS AND METHODS: The set-up accuracy measured by daily online volumetric imaging was retrospectively reviewed for the first 15 patients with HNC treated on the TomoTherapy unit at Addenbrooke's Hospital. For each fraction, megavoltage computed tomography was carried out, any discrepancy from the planning scan was noted, and corrected, before treatment. These data were used to evaluate imaging correction protocols using three different action levels. The first three fractions were imaged and used to correct for systematic error, using a 5 mm action level (5 mmAL), a 3 mm action level (3 mmAL), and no action level (NAL). All imaging strategies were applied, to assess the number of fractions that would potentially have exceeded a 5 and 3 mm margin. Systematic and random errors were calculated for the population, assuming the NAL protocol had been applied, and minimum CTV-PTV margins, required to allow for errors attributable only to set-up, were calculated using van Herk's formula. RESULTS: In total, 490 fractions were analysed. Using a 5 mmAL imaging protocol, potentially 198/490 fractions (40%) were outside a 5 mm CTV-PTV margin and 400/490 (82%) were outside a 3 mm margin. Using a 3 mmAL imaging protocol, potentially 67/490 fractions (14%) were outside a 5 mm CTV-PTV margin and 253/490 (52%) were outside a 3 mm margin. A small systematic error was identified in the system; once corrected this would improve these results. Using the NAL imaging protocol, potentially 31/490 fractions (6%) were outside a 5 mm CTV-PTV margin and 143/490 fractions (29%) were outside a 3 mm margin. Estimated minimum CTV-PTV margins to account only for set-up errors, with three-fraction image-guided radiotherapy and a NAL protocol, were 2.8, 3.1 and 4.1 mm in the mediolateral, superior-inferior and anterior-posterior directions, respectively. CONCLUSION: Reducing the action level at which the systematic error is corrected improves the probability of treatment delivery accuracy. Using the NAL correction protocol reduces the number of fractions that have set-up displacements outside a 5 mm CTV-PTV margin. Although a 5 mm margin is probably sufficient for standard HNC radiotherapy, change to a 3 mm margin is not favoured at our centre without access to daily image-guided radiotherapy.

High-dose radiotherapy in the management of chordoma and chondrosarcoma of the skull base and cervical spine: Part 1--Clinical outcomes.

AIMS: Patients with chordoma and chondrosarcoma in the skull base present a complex multidisciplinary problem. These tumours are rare and occur in difficult anatomical regions. We reviewed the local control and survival of patients treated in our centre. MATERIALS AND METHODS: Between 1996 and 2005, 12 adult cases of chordoma (nine) and chondrosarcoma (three) in the skull base or cervical spine were treated in our centre. The median follow-up is currently 38 months. One patient was treated with palliative intent. In 10 cases the prescription dose was 65 Gy in 39 fractions. The target volumes were measured, and the target maximum and minimum doses and the equivalent uniform dose (EUD) for the phase I plans were recorded. RESULTS: Local control was achieved in 11 of 12 cases. One chordoma patient failed locally, and one other died of metastatic disease despite local control. The 3- and 5-year cause-specific survival for the series was 88 and 75%, respectively. The mean phase I planning target volume (PTV) was 120.4 cm(3). The median minimum dose in the phase I PTV was 81.0%. The median EUD (expressed as a percentage of the prescribed dose) for the phase I PTV, calculated using a value for the exponent a of -15, was 98.3%. The phase I EUD was below 80% in two of the 12 cases. CONCLUSIONS: Our results confirm a need for aggressive local surgery and high-dose radiotherapy, and endorse multidisciplinary working. Although charged particle therapy is accepted as providing optimal treatment plans, in eight of our patients travel abroad would not have been feasible. This series provides encouraging results for carefully planned photon conformal radiotherapy, carried out in close collaboration with a specialist surgical team.

Fractionated conformal radiotherapy in vestibular schwannoma: early results from a single centre.

AIMS: To assess the local control and cranial nerve toxicity in vestibular schwannoma patients treated with fractionated conformal radiotherapy delivered using a linear accelerator. MATERIALS AND METHODS: Ninety-five patients were referred for consultation to the Oncology Department in Addenbrookes Hospital between 1996 and 2005. The 42 cases who received fractionated conformal radiotherapy are the subject of this analysis. All patients had radiological or symptomatic progression. Conformal radiotherapy was prescribed at 50Gy in 30 fractions over 6 weeks, delivered using a linear accelerator. Patients were immobilised using either a beam direction shell or a Gill Thomas Cosman relocatable stereotactic head frame. RESULTS: The median age was 63 years (range 28-81) with 57% men. The average tumour size was 21.5mm on magnetic resonance imaging. Before treatment, 20 (48%) patients were deemed to have useful hearing on the affected side. The median follow-up was 18.6 months (range 0.3-6.5 years) and the actuarial local control rate at 2.5 years was 96.9% (one patient progressed after treatment). In previously hearing patients, the actuarial rate of useful hearing preservation was 100%, and the rate of mild hearing loss was 20% at 1 year and 26.7% at 2.5 years of follow-up. There were five neurofibromatosis type 2 patients treated, two of whom had useful hearing before radiotherapy. In one patient this was affected, with a 20dB loss, although he still has useful hearing. In those with normal facial nerve function before radiotherapy (n=40), this was preserved in 96.8% at 2.5 years. Trigeminal nerve function was preserved in all patients (n=38) who had normal nerve function before radiotherapy. CONCLUSION: Although follow-up was relatively short in this single institution series, fractionated linear accelerator radiotherapy gave excellent local control, useful hearing preservation and retained cranial nerve function in vestibular schwannoma.

Mathematical modelling of survival of glioblastoma patients suggests a role for radiotherapy dose escalation and predicts poorer outcome after delay to start treatment.

AIMS: The outcome of patients with glioblastoma (GBM) remains extremely poor. We have developed a mathematical model, using pathological and radiation biology concepts, to assess the detrimental effect of delay to start radiotherapy, the possible benefit from dose escalation, and to extract biological data from clinical data. MATERIALS AND METHODS: Survival data were available for 154 adult patients with GBM treated in our centre with curative intent to a dose of 60 Gy in 30 fractions between 1996 and 2002. Survival data for 129 patients from the 60 Gy arm of the MRC BR02 randomised trial of radiotherapy dose were obtained for comparison. The model generates the equivalent of individual patients with a brain tumour, and produces an explicit outcome, either death or survival. The tumour, assumed to be growing exponentially, causes normal cell damage in the brain, and death occurs when the number of normal brain cells falls below a critical level. The outcome for an individual patient is determined by values of the variables assigned by the model. Parameters for the single patient include tumour doubling time, surviving fraction of tumour cells after each fraction of radiotherapy, and a waiting time from presentation to the start of radiotherapy. A surrogate for performance status is implemented, using a rule that rejects patients whose tumours are too advanced at presentation to be suitable for radical radiotherapy. Values for the parameters that determine individual patient outcome are randomly assigned from a set of probability distributions, using Monte Carlo simulation. The simulation constructs survival results for a population, typically 2000 individuals. The descriptors of the probability distributions that are used to determine the parameters that define the patient characteristics are adjusted to optimise the fit of the modelled population to real clinical data, using a combination of folding polygon and simulated annealing techniques. RESULTS: The model fits the clinical data well. The results suggest that the surviving fraction of tumour cells after a radiation dose of 2 Gy (SF2) does influence patient outcome. The mean in vivo SF2 for the Addenbrooke's data is 0.80, implying that hypoxia is a serious problem in radiotherapy for GBM. The Addenbrooke's data suggest a mean tumour doubling time of 24 days, so that a delay to start radiotherapy would be expected to have an adverse effect. Considering patients by treatment intent, median survival plummets as delay increases, and almost no patients survive long term after a 70-day delay. Radiotherapy dose escalation has an important predicted effect on survival. Assuming that the treatment could be delivered safely, a dose of 74 Gy, given at 2 Gy/fraction, would extend the survival of all patients. The proportion of long-term survivors would increase, from 2.4% with 60 Gy, to 6.4% with 74 Gy. The model can be used to derive gamma50, which has a value of 0.42, lower than the typical value of 1-2. CONCLUSION: Using the model, we have extracted biological information from clinical data. The model could be used to assess the potential benefit, or lack of benefit, from a proposed radiotherapy trial, and to estimate the necessary size. It shows that a single modality is unlikely to achieve a major improvement in long-term survival, although radiotherapy dose escalation should have a role, provided it can be given safely. The model could be extended to include chemotherapy, bio-reductive drugs, or gene therapy.

Diffusion tensor imaging: possible implications for radiotherapy treatment planning of patients with high-grade glioma.

AIMS: Radiotherapy treatment planning for high-grade gliomas (HGG) is hampered by the inability to image peri-tumoural white-matter infiltration. Diffusion tensor imaging (DTI) is an imaging technique that seems to show white-matter abnormalities resulting from tumour infiltration that cannot be visualised by conventional computed tomography or magnetic resonance imaging (MRI). We propose a new term, the image-based high-risk volume (IHV) for such abnormalities, which are distinct from the gross-tumour volume (GTV). For IHV based on DTI, we use the term IHVDTI. This study assesses the value of DTI for the individualisation of radiotherapy treatment planning for patients with HGG. METHODS: Seven patients with biopsy-proven HGG were included in a theoretical planning exercise, comparing standard planning techniques with individualised plans based on DTI. Standard plans were generated using a 2.5 cm clinical target volume (CTV) margin added to the GTV. For DTI-based plans, the CTV was generated by adding a 1 cm margin to the IHVDTI. Estimates of normal tissue complication probability (NTCP) were calculated and used to estimate the level of dose escalation that could be achieved using the DTI-based plans. RESULTS: The use of DTI resulted in non-uniform margins being added to the GTV to encompass areas at high risk of tumour involvement, but, in six out of seven cases, the IHVDTI was encapsulated by the standard CTV margin. In all cases, DTI could be used to reduce the size of the planning-target volume (PTV) (mean 35%, range 18-46%), resulting in escalated doses (mean 67 Gy, range 64-74 Gy), with NTCP levels that matched the conventional treatment plans. CONCLUSION: DTI can be used to individualise radiotherapy target volumes, and reduction in the CTV permits modest dose escalation without an increase in NTCP. DTI may also be helpful in stratifying patients according to the degree of white-matter infiltration.