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.

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.

A novel algorithm for the morphometric assessment of radiotherapy treatment planning volumes.

Quantitative assessment of target volume contouring in radiotherapy treatment planning is an important aspect of quality assessment and educational exercises. The Conformity Index (CI) is a volume-based statistic frequently used for this purpose. Although the CI is relatively simple to understand and can be calculated using most treatment planning systems, it does not provide any information on the differences in shape between the two volumes. We present a new morphometric (shape-based) statistic known as the "mean distance to conformity" (MDC). For a specific volume that is being evaluated against a reference volume, the MDC represents the average distance that all outlying points in the volume must be moved in order to achieve perfect conformity with the reference volume. The MDC comprises a component related to under-contouring (where the evaluation volume is smaller than the reference volume) and a component related to over-contouring (where the evaluation extends beyond the reference volume). Furthermore, voxel-by-voxel information on conformity errors can also be displayed using a volume-error histogram. Calculation of MDC statistics is achieved using a three-dimensional grid search algorithm. By using a range of scenarios comprising both theoretical and actual clinical volumes, we demonstrate the increased utility of the MDC for the detection of contouring errors.

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.

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.

Conformal rotation therapy with central axis beam block is a feasible alternative to intensity-modulated radiotherapy for chordomas of the cervical spine.

AIMS: Paraspinal tumours, such as chordoma, represent a treatment challenge for oncologists, requiring high dose to the target volume without exceeding the tolerance dose of the spinal cord. Intensity-modulated radiotherapy (IMRT) is helpful in achieving sharp dose gradients and conformation of dose to the target volume. We present a simpler technique--conformal rotation therapy with a central axis beam block (CRT + BB), which can provide similar dose distributions. MATERIALS AND METHODS: A patient with a cervical chordoma developed postoperative recurrence and was treated with high-dose palliative radiotherapy. Treatment was delivered using CRT + BB, with three fixed beams and three coplanar arcs. A dose of 62 Gy in 31 fractions was delivered to the 100% isodose, giving a maximum spinal cord dose of 49.6 Gy. The patient relapsed 2 years later, and was re-treated using the same technique to a dose of 57 Gy in 30 fractions. Estimates of spinal cord repair rates in primates were used to determine the tolerance dose of the spinal cord for re-treatment. The patient remained well for a further 25 months before developing local recurrence, which was treated with palliative chemotherapy. RESULTS: Re-treatment plans using CRT + BB and IMRT were compared. Dose-volume histograms show equivalence of dose to the spinal cord, although the IMRT plan delivered a slightly higher dose to tumour and lower dose to surrounding soft tissues. CONCLUSION: Treatment using CRT + BB requires careful planning and discussion with neurosurgeons before surgery. The normal curvature of the cervical spine must be eliminated if possible, and the patient must be immobilised with the neck horizontal. If these geometric constraints can be satisfied, then CRT + BB can be used as a safe and effective alternative treatment to IMRT for tumours at this site.

Accuracy of a relocatable stereotactic radiotherapy head frame evaluated by use of a depth helmet.

In high precision radiotherapy, the more accurately the patient can be relocated, the smaller the clinical to planning target volume margin can be, with reduction in the volume of normal tissue irradiated. The Gill-Thomas-Cosman (GTC) relocatable stereotactic head frame provides immobilization of the patient which is highly reproducible. A depth helmet and measuring probe were used to confirm the accuracy of relocation of 31 patients treated in the GTC frame. The measurements were processed in a spreadsheet developed to calculate the size of the patient's displacement as a vector. Twenty-seven patients received fractionated stereotactically-guided conformal radiotherapy, and 4 single fraction stereotactic radiosurgery, amounting to 564 measurement episodes. The accuracy was extremely good, and considerably more accurate than standard thermoplastic head shells. Ninety-two percent of the displacement vectors were less than 2 mm, and 97% less than 2.5 mm. Considering each dimension separately, the largest mean displacement was 0.4 mm in the superior-inferior direction. Accuracy was constant through a fractionated course for most patients, but prediction based on measurements from the first few fractions was not reliable. Results were dependent on patient selection, with worse reproducibility in patients with neurological deficits, or difficulty cooperating. The depth helmet measurements detected a loosened mouth bite in one patient and allowed repositioning to be verified without the need for the simulator. Total treatment time, including use of the depth helmet to verify treatment position, is quicker (mean 15.7 min) than using portal films. The depth helmet, used in conjunction with the vector displacement spreadsheet, provides a simple way to define the CTV-PTV margin. For fractionated stereotactic radiotherapy we use a 3 mm CTV-PTV margin. This system could assist technology transfer to centres starting stereotactic radiotherapy using the GTC frame.

A tool to measure radiotherapy complexity and workload: derivation from the basic treatment equivalent (BTE) concept.

Radiotherapy workload is poorly represented by simple parameters of patients, fractions or fields treated because these do not contain any measure of treatment complexity. However, complexity is increasing and there is an urgent need to quantify this. We have evaluated the basic treatment equivalent (BTE) model as a measure of radiotherapy workload and complexity. Radiotherapy treatment times, from the patient entering to exiting the treatment room maze, were measured for 1298 treatment sessions on 269 patients. The data were used to assess the original model and derive three new models for predicting treatment duration. The most complicated, the 'Addenbrooke's complex model', contained two additional predictor variables, including 'site/technique', in a linear additive form. Before the study, the department used a standard treatment appointment time of 10 minutes. However, 50% of the measured treatments took longer than 10 minutes, (mean 10.9). Summed over the working day, this discrepancy indicates that a standard 10-minute appointment is a poor basis for scheduling radiotherapy. The original BTE model was effective in predicting treatment times, although this was improved by refinement of the model. The Addenbrooke's complex model correctly predicted 70% of treatment times to within 2 minutes (55% for the original BTE model), 80% to within 2.5 minutes and 95% to within 4.7 minutes. The percentage of the variation in observed times accounted for by the model is 59.4%. The models can represent radiotherapy complexity, can improve scheduling on linear accelerators, and are likely to be applicable to other departments. They are thus tools to assess the impact of changes in complexity from new techniques, trial protocols (e.g. the Medical Research Council prostate radiotherapy trial RTO1), and possible time saving from advanced technology such as multileaf collimators (MLCs) or automated machine set-up. The replacement of manually-lifted shielding blocks by MLCs should save 1.1-1.5 minutes for a three- or four-field pelvic plan (i.e. 12%-13%). The models could also be used to aid planning for future linear accelerator provision and for costing radiotherapy treatment.

Fragmentation of biliary calculi in 71 patients by use of intracorporeal electrohydraulic lithotripsy.

PURPOSE: Failure of percutaneous or endoscopic removal of biliary calculi is often associated with impacted stones or stones larger than 1.5 cm. In these difficult cases, intracorporeal electrohydraulic lithotripsy (EHL) is a method that allows large stones to be fragmented and removed percutaneously or endoscopically. In this study, the authors expand their experience with EHL and further evaluate the safety and efficacy of this technique to remove biliary tract calculi. PATIENTS AND METHODS: Intracorporeal electrohydraulic lithotripsy was used to treat 71 patients with calculi in the bile ducts (n = 35) or gallbladder (n = 36). Access was obtained by means of a surgical T-tube tract (n = 16), percutaneous transhepatic biliary drainage (n = 14), percutaneous cholecystostomy (n = 36), an intraoperative approach during common duct exploration (n = 2), and at endoscopic retrograde cholangiopancreatography (n = 3). RESULTS: EHL lithotripsy was effective in fragmenting all biliary stones in 69 of the 71 patients (97%). All of the stone fragments were removed in 67 of these 69 patients (94%). Major complications, including bile peritonitis and gallbladder necrosis, occurred in five patients; however, all major complications were related to the initial percutaneous drainage or tract dilation. No significant complications were directly attributable to the EHL procedure. CONCLUSION: Intracorporeal EHL is a safe and effective method that can be used to improve the success of percutaneous and endoscopic biliary calculi removal.

The "total solution" for total hip replacement surgery.

Despite the great alleviation in suffering produced by total hip replacement surgery, some caution is indicated. Many of the patients who undergo surgery still present problems some time after the operation and for which there is no obvious or adequate medical or engineering explanation. It is therefore suggested that no report on such surgery is complete without regard for patients' expectations, patients' satisfaction and without common agreement by surgeons on what can be expected from the operation. This paper highlights the importance of patients' and surgeons' expectations and the need for all to be aware of the influence of such expectations. If also suggests that surgeons rely heavily on their own judgements as to what state patients should be in prior to surgery. If the solution for such a radical measure is to be total for the patient, then patients' feelings and judgements should also be considered.

Patients' expectations in relation to outcome of total hip replacment surgery.

The importance of expectations has been assessed by giving 88 patients who had undergone total hip replacement surgery a series of visual analogue scales to provide a pain score, a 5-point rating scale to assess their remembered expectations, and an interview to establish clinical, functional, social, and psychological data. Patients generally had high expectations, but only 55% had their expectations fulfilled. Despite this, 86% claimed the operation to be successful, though when questioned more closely patients noted a certain amount of displeasure about the outcome. Further analysis revealed that, when the sample was split into 2 groups of fulfilled and unfulfilled expectations, significant differences were noted in that the quality of life enjoyed by the former group was greater than that enjoyed by the latter group. This finding suggests that the notion of 'success' is not as effective as the notion of 'expectations' as a measure of the outcome of total hip replacement surgery.

A simple goniometer for measuring hip function.

A goniometer was designed and developed in an attempt to find an objective method of measuring hip flexion and extension in walking as as indication of hip function. Existing goniometers were found to be inadequate for clinical and research use because either they did not provide sufficient information or the information they provided was more than necessary, requiring bulky and time-consuming power devices. The present goniometer is a compromise, providing a quick and easy-to-use clinical and research tool which measures total flexion and extension in walking.

What shall we teach undergraduates?

The opinions of 600 randomly selected doctors on what should be taught to undergraduates in clinical years were analysed. The respondents gave a high priority to general medicine, paediatrics, general surgery, casualty, and gynaecology, but a low priority to forensic medicine, plastic surgery, radiotherapy, anaesthetics, radiology, and rehabilitation medicine. Doctors thought that these should be taught to postgraduates. The two major groupings of doctors--general practitioners and consultants--gave essentially the same priorities. Undergraduate curricula cannot include all major specialities, so the results of this analysis may provide a useful basis for selecting the most suitable subjects. Criteria for including other specialties might be the ability and enthusiasm of the teachers and well-thought-out and academically sound teaching programmes.