AIMS:To assess in patients with 1-10 brain metastases, each of which has been treated by neurosurgery or stereotactic radiosurgery, whether hippocampal sparing whole brain radiotherapy (HS-WBRT) better spares neurocognitive function (NCF) than standard WBRT. Further, to assess whether a phase III randomised trial of HS-WBRT would be feasible in the UK. MATERIALS AND METHODS:A multicentre, randomised, open label phase II trial was undertaken, randomising patients to 30Gy in 10 fractions of WBRT or HS-WBRT. The primary endpoint was decline in Total recall using Hopkins Verbal Learning Test Revised (HVLT-R) at 4 months post treatment. To assess this, we aimed to recruit 84 patients over 3 years. Secondary endpoints included further measures of NCF, quality of life, duration of functional independence, local control of treated metastases, development of new metastases, disease control within the hippocampal regions, overall survival, steroid and antiepileptic medication requirements, and toxicity. RESULTS:The trial closed prematurely due to slower than anticipated recruitment. From April 2016 to January 2018, 23 patients were randomised. Follow up was a median of 25 months. Fifteen patients (6 WBRT, 9 HS-WBRT) were assessed for the primary endpoint; of these, 1 in each arm experienced significant decline in the 4-month HVLT-R Total recall score (p = 0.8). Patients in the HS-WBRT arm experienced less insomnia (p < 0.01) and drowsiness (p < 0.01). There were no differences in other secondary endpoints. CONCLUSION:A phase III randomised trial of HS-WBRT was shown not to be feasible at this time in the UK. As most randomised trials of HS-WBRT reported to date share common endpoints, including NCF, an individual patient data meta-analysis should be undertaken.

Effects of ADI-PEG20 on the folate pathway

BACKGROUND:Effective treatment for patients at least 70 years with newly diagnosed glioblastoma remains challenging and alternatives to conventional cytotoxics are appealing. Autophagy inhibition has shown promising efficacy and safety in small studies of glioblastoma and other cancers.METHODS:We conducted a randomized phase II trial to compare radiotherapy with or without hydroxychloroquine (2:1 allocation). Patients aged at least 70 years with newly diagnosed high-grade glioma deemed suitable for short-course radiotherapy with an ECOG performance status of 0-1 were included. Radiotherapy treatment consisted of 30 Gy, delivered as 6 fractions given over 2 weeks (5 Gy per fraction). Hydroxychloroquine was given as 200 mg orally b.d. from 7 days prior to radiotherapy until disease progression. The primary endpoint was 1-year overall survival (OS). Secondary endpoints included progression-free survival (PFS), quality of life, and toxicity.RESULTS:Fifty-four patients with a median age of 75 were randomized between May 2013 and October 2016. The trial was stopped early in 2016. One-year OS was 20.3% (95% confidence interval [CI] 8.2-36.0) hydroxychloroquine group, and 41.2% (95% CI 18.6-62.6) radiotherapy alone, with a median survival of 7.9 and 11.5 months, respectively. The corresponding 6-month PFS was 35.3% (95% CI 19.3-51.7) and 29.4% (95% CI 10.7-51.1). The outcome in the control arm was better than expected and the excess of deaths in the hydroxychloroquine group appeared unrelated to cancer. There were more grade 3-5 events in the hydroxychloroquine group (60.0%) versus radiotherapy alone (38.9%) without any clear common causation.CONCLUSIONS:Hydroxychloroquine with short-course radiotherapy did not improve survival compared to radiotherapy alone in elderly patients with glioblastoma.

AUTHORS: Peter E. Hall, Rachel Lewis, Nelofer Syed, Richard Shaffer, Jane Evanson, Stephen Ellis, Matthew Williams, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Fiona Harris, Raj Jena, Tomasz Matys, Sarah Jefferies, Kate Smith, Bor-Wen Wu, John Bomalaski, Timothy Crook, Kevin O’Neill, Dimitris Paraskevopoulos, Ramsay Khadeir, Michael T. Sheaff, Simon Pacey, Piers N. Plowman, and Peter W. Szlosarek

AbstractPurpose: Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. Patients and Methods: We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16–06/17) to receive weekly ADI-PEG20 36 mg/m2 intramuscularly plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy. Results: Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti–ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5–20.8) and overall survival was 6.3 months (95% CI, 1.8–9.7). Conclusions: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.

e14085 Background: Patients (pts) with recurrent HGGs are usually managed with alkylating chemotherapy +/- bevacizumab. However, prognosis remains poor with an overall survival (OS) of 7-9 months. Preclinically, we showed that HGGs are a target for arginine depletion with Pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-ve HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. Methods: We expanded a phase 1 trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS), which noted activity in aggressive thoracic cancers, to pts with relapsed HGGs (clinicaltrials.gov NCT02029690). Pts with ASS1-ve recurrent HGGs were enrolled (01/16 – 06/17) to receive ADI-PEG20 weekly at the maximum tolerated dose of 36 mg/m2 i.m. plus PEM 500 mg/m2 and CIS 75 mg/m2 i.v. every 3 weeks for up to 6 cycles. Pts with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability and preliminary estimates of activity. Additional endpoints included pharmacodynamics, immunogenicity, OS, and ASS1/ASL epimutations. Results: 10/19 ASS1-ve heavily pre-treated pts were enrolled onto ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events (AEs) being CTCAE v4.03 grade 1-2; 7 pts (70%) had at least one grade 3 or 4 AE with neutropenia (40%) and thrombocytopenia (30%). The best response was stable disease by RECIST 1.1 and partial response (n = 1; 10%) by Response Assessment in Neuro-oncology (RANO) criteria. The median (95% CI) OS was 6.5 (1.8, 9.7) months. Plasma arginine and the anti-ADI-PEG20 antibody titer were suppressed with a reciprocal increase in citrulline. Two pts are alive and 1 continues 16 months on ADI-PEG20 as 3rd-line therapy for a de novo glioblastoma multiforme. Epimutations in ASS1 and/or ASL were detectable in pts’ tumors consistent with prior studies. Conclusions: ADIPEMCIS was well tolerated and compares favorably to historical controls in recurrent HGG. A randomized, phase II trial comparing ADIPEMCIS with alkylating drugs at first relapse is planned (ATOMIC-G). Clinical trial information: NCT02029690.

[3], but this has not been standardised across UK training programmes, and its extent and quality vary between radiotherapy centres. We therefore carried out a project aiming to improve the radiotherapy induction programme in our centre. A LEAN methodology was used to explore the issues around radiotherapy induction. As a result, a radiotherapy induction programme consisting of a radiotherapy department orientation tour, hands-on training on the radiotherapy treatment planning system and palliative radiotherapy planning was developed and implemented with a radiotherapy induction pack. An online survey of trainees/speciality doctors was conducted before and after the implementation of the programme. Thirteen doctors participated in the baseline and postradiotherapy induction programme surveys. After the implementation of radiotherapy induction, doctors’ agreement on good induction to the radiotherapy treatment planning system, radiotherapy planning workflow and radiotherapy departmental structure and contacts improved from 22 to 75%, 33 to 100% and 22 to 100%, respectively. All trainees had their passwords and completed their signature forms at induction. Of the 13 doctors, 92% agreed that a mandatory radiotherapy induction programme before clinical placement(s) at a new centre would be a good idea and 61% indicated that a regional-level radiotherapy induction programme would be useful.

Most radiotherapy (RT) involves the use of high doses (>50 Gy) to treat malignant disease. However, low to intermediate doses (approximately 3-50 Gy) can provide effective control of a number of benign conditions, ranging from inflammatory/proliferative disorders (e.g. Dupuytren's disease, heterotopic ossification, keloid scarring, pigmented villonodular synovitis) to benign tumours (e.g. glomus tumours or juvenile nasopharyngeal angiofibromas). Current use in UK RT departments is very variable. This review identifies those benign diseases for which RT provides good control of symptoms with, for the most part, minimal side effects. However, exposure to radiation has the potential to cause a radiation-induced cancer (RIC) many years after treatment. The evidence for the magnitude of this risk comes from many disparate sources and is constrained by the small number of long-term studies in relevant clinical cohorts. This review considers the types of evidence available, i.e. theoretical models, phantom studies, epidemiological studies, long-term follow-up of cancer patients and those treated for benign disease, although many of the latter data pertain to treatments that are no longer used. Informative studies are summarized and considered in relation to the potential for development of a RIC in a range of key tissues (skin, brain etc.). Overall, the evidence suggests that the risks of cancer following RT for benign disease for currently advised protocols are small, especially in older patients. However, the balance of risk vs benefit needs to be considered in younger adults and especially if RT is being considered in adolescents or children.

1STEPHANIE R MCKEOWN, MA, PhD, 2PAUL HATFIELD, FRCR, PhD, 2ROBIN JD PRESTWICH, FRCR, PhD, 3RICHARD E SHAFFER, MRCP, FRCR and 4ROGER E TAYLOR, FRCP, FRCR School of Biomedical Sciences, University of Ulster, Coleraine, UK Leeds Cancer Centre, St James’s University Hospital, Leeds, UK St Luke’s Cancer Centre, Royal Surrey County Hospital, Guildford, UK College of Medicine, Swansea University, South West Cancer Centre, Swansea, UK

Most patients treated by external beam radiotherapy are being treated for cancer. However, historically, many patients have been treated with radiotherapy for a variety of benign (i.e. non-neoplastic) conditions. Furthermore, radiotherapy is also used for the treatment of a wide range of benign tumours [[1]Seegenschmiedt M.H. Makoski H.-B. Trott K.-R. Radiotherapy for non-malignant disorders. Contemporary concepts and clinical results. Springer, Berlin2008Crossref Google Scholar]. In recent years, the Faculty of Clinical Oncology of the Royal College of Radiologists has become aware that, within the UK, the use of radiotherapy for benign conditions has declined, with varying and often small patient numbers being treated. This editorial aims to highlight this issue and to summarise a recent report by a Royal College of Radiologists working group [[2]The Royal College of Radiologists. A review of the use of radiotherapy in the UK for the treatment of benign clinical conditions and benign tumours. London: The Royal College of Radiologists, 2015.Google Scholar]. The report is designed to inform the development of a more evidence-based and equitable strategy for the use of radiotherapy, where it has proven efficacy, across all parts of the UK. Furthermore, the document will serve as a 'handbook' for clinicians to consult when referred a patient with a benign condition. It was agreed that the review should include the use of radiotherapy for most benign conditions historically treated by external beam radiotherapy and selected conditions treated by stereotactic (brain) radiotherapy. The review also includes selected benign tumours, generally those that are rarely treated by radiotherapy and where the literature is not well known (see Table 1).Table 1Individual diseases reviewedDisease groupDiseases reviewed with the number of centres out of 25 respondents reporting treatmentHead and neckParagangliomas (11)Juvenile nasopharyngeal angiofibroma(4) Pleomorphic adenoma (N)Sialorrhea (2)EyeThyroid eye disease (19)Orbital pseudotumour (4)Pterygium (0)Age-related macular degeneration (0)Choroidal haemangioma (0)Central nervous systemGrade 1 meningioma (N)Cerebral arterio-venous malformations (N)Trigeminal neuralgia (1)Vestibular schwannoma (8)Orthopaedic/musculoskeletalDupuytren's disease of the hand (4)Plantar fibromatosis of the foot (Ledderhose disease) (N)Plantar fasciitis (1)Peyronie's disease (0)Heterotopic ossification of the hip (14)Pigmented villonodular synovitis (PVNS) (4)Vertebral haemangioma (1)Aneurbysmal bone cyst (1)Skin/soft tissuesKeloid scarring (15)Lentigo maligna (N)Hidradenitis suppurativa (1)Psoriasis (N)Chronic eczema (1)Prevention and treatment of gynaecomastia due to endocrine therapy for prostate cancer (N)N – not included in the original questionnaire survey, but reviewed in the main document. Open table in a new tab N – not included in the original questionnaire survey, but reviewed in the main document. In order to provide an estimate of the current use of radiotherapy for benign disease, a questionnaire survey of radiotherapy departments throughout the UK was undertaken in 2012. This requested the numbers of patients treated per annum for a range of benign tumours and non-malignant conditions. Responses were received from 25/61 departments (41%). This showed a core of activity in many centres, particularly for some benign tumours. When radiotherapy was used for non-malignant conditions, those most commonly treated were heterotopic ossification, keloid scarring, thyroid eye disease and Dupuytren's contracture. The large activity for treatment of trigeminal neuralgia (in one centre) and vestibular schwannoma were related to treatment with stereotactic radiosurgery. One important feature was the wide variation in practice across the UK. For example, one centre annually treated about 64 patients with keloid scarring, whereas most others treated none. As the degree of variation was not clear before the survey, potential reasons that might explain the inter-departmental variation were not asked for. Details of numbers treated for individual conditions are provided in the main document. There are conditions that are considered to be more appropriate for treatment than others, for example most departments (19/25; 76%) reported treating patients with thyroid eye disease, but no department reported treating patients with pterygium, although this was often treated up to the 1980s. The review includes discussion of the radiobiological principles of radiotherapy for benign conditions, including the potential influence of a wide range of radiotherapy-related and patient-specific factors. The exposure of normal tissues to ionising radiation in the intermediate dose range (about 20–40 Gy) is discussed, including the vascular, stromal and anti-inflammatory sequelae. Broadly, there are two basic mechanisms that can be exploited. First, the anti-proliferative effect of radiotherapy [3Rodemann H.P. Blaese M.A. Responses of normal cells to ionizing radiation.Semin Radiat Oncol. 2007; 2: 81-88Abstract Full Text Full Text PDF Scopus (153) Google Scholar, 4Westbury C.B. Yarnold J.R. Radiation fibrosis - current clinical and therapeutic perspectives.Clin Oncol. 2012; 10: 657-672Abstract Full Text Full Text PDF Scopus (71) Google Scholar, 5Yarnold J. Brotons M.C. Pathogenetic mechanisms in radiation fibrosis.Radiother Oncol. 2010; 1: 149-161Abstract Full Text Full Text PDF Scopus (440) Google Scholar], which, for example, can be exploited to reduce the risk of heterotopic ossification after hip replacement. Second, the anti-inflammatory effect [[6]Arenas M. Sabater S. Hernández V. et al.Anti-inflammatory effects of low-dose radiotherapy. Indications, dose, and radiobiological mechanisms involved.Strahlenther Onkol. 2012; 11: 975-981Crossref Scopus (103) Google Scholar] can be used for the treatment of a number of soft tissue inflammatory conditions, such as thyroid eye disease. The radiotherapy doses used for the treatment of benign conditions are often well below the range used to treat cancer. For example, a so-called 'anti-inflammatory dose' of radiotherapy is often around 20 Gy in 10 fractions or its equivalent. The highest doses used are for the treatment of benign tumours (40–50 Gy in 2 Gy fractions) and, consequently, for most patients acute toxicity is rarely a problem. The most important age-dependent side-effect for these radiation doses is the potential increased risk of radiation-induced cancer (RIC). This is considered for a range of tissues and is further detailed in the discussion of the individual indications. Interpretation of the literature on radiotherapy for benign conditions is problematic. Much of the evidence is based on case reports and single institution case series, although randomised studies and systematic reviews do exist. Many of the more substantial studies using radiation in the dose range applicable to treating benign disease relate to regimens no longer in use and delivered with obsolete equipment, e.g. ankylosing spondylitis [7Court-Brown W.M. Doll R. Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis.Br Med J. 1965; : 1327-1332Crossref Scopus (370) Google Scholar, 8Darby W.C. Doll R. Gill S.K. et al.Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis.Br J Cancer. 1987; 55: 179-190Crossref PubMed Scopus (279) Google Scholar, 9Weiss H.A. Darby S.C. Doll R. Cancer mortality following X-ray treatment for ankylosing spondylitis.Int J Cancer. 1994; 9: 327-338Crossref Scopus (190) Google Scholar]. Consequently, extrapolation to current treatment indications with modern techniques is problematic. Although these groups have been followed-up for many years, many other studies tend to have relatively short-term follow-up. This may be a problem for younger individuals and especially children in terms of balancing the long-term benefits and risks. For some conditions evidence is more complete; for example, there have been randomised trials into the benefits of radiotherapy for treating pterygium [10Jurgenliemk-Schulz I.M. Hartman L.J. Roesink J.M. et al.Prevention of pterygium recurrence by postoperative single-dose beta-irradiation: a prospective randomized clinical double-blind trial.Int J Radiat Oncol Biol Phys. 2004; 59: 1138-1147Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 11Simsek T. Gunalp I. Atilla H. Comparative efficacy of beta-irradiation and mitomycin-C in primary and recurrent pterygium.Eur J Ophthalmol. 2001; 11: 126-132PubMed Google Scholar] and there is ongoing clinical research in the field of radiotherapy for macular degeneration. The decline in the use of radiotherapy for benign conditions is probably multifactorial, but important factors would be increased availability of alternative medical therapies, advances in surgery and also concerns as to the potential risk, if very small, of RIC. This is exemplified by the increased incidence of leukaemia after radiotherapy for ankylosing spondylitis [7Court-Brown W.M. Doll R. Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis.Br Med J. 1965; : 1327-1332Crossref Scopus (370) Google Scholar, 8Darby W.C. Doll R. Gill S.K. et al.Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis.Br J Cancer. 1987; 55: 179-190Crossref PubMed Scopus (279) Google Scholar, 9Weiss H.A. Darby S.C. Doll R. Cancer mortality following X-ray treatment for ankylosing spondylitis.Int J Cancer. 1994; 9: 327-338Crossref Scopus (190) Google Scholar]. However, bearing in mind the age range of most patients and the relatively low radiotherapy doses used, often to peripheral areas of the body, the risks of radiotherapy may be lower than the risks of alternative therapies such as anti-inflammatory drugs or other interventions. Clearly, the risk of RIC is an issue that needs to be discussed with patients. Indeed, it is also a factor that may influence the judgement of referring clinicians, for example ophthalmologists, dermatologists and orthopaedic surgeons. As the factors governing the risk of RIC are complex, hard to estimate and often very patient specific (e.g. age, site of irradiation, dose, etc.), guidance is provided as to the most important factors that should be used to advise patients and referers [12Berrington de Gonzalez A. Curtis R.E. Kry S.F. et al.Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries.Lancet Oncol. 2011; 12: 353-360Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar, 13Berrington de Gonzalez A. Gilbert E. Curtis R. et al.Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship.Int J Radiat Oncol Biol Phys. 2013; 86: 224-233Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 14Trott K.R. Kamprad F. Estimation of cancer risks from radiotherapy of benign diseases.Strahlenther Onkol. 2006; 182: 431-443Crossref PubMed Scopus (89) Google Scholar]. Unfortunately, only in a few instances is there any substantive quantitative evidence of RIC risk, as the numbers required to estimate risk are very large and the numbers who currently receive radiotherapy for many of these conditions is relatively small; additionally they would require very long follow-up to detect RIC. With these provisos, an attempt has been made to identify the risk to inform discussion with patients considered for radiotherapy for a wide range of benign conditions (Table 1). The limited use of radiotherapy for benign conditions in the UK is in contrast to practice in Germany. This has been informed by the reports of the German Working Group on Radiotherapy of Benign Diseases, which has extensively reviewed the use of radiotherapy for benign disease in a series of Patterns of Care Study reports. The conclusions were that radiotherapy was a well-accepted modality that was relatively often used for a wide range of benign diseases; however, significant departmental and geographical variations in its use were evident. At that time (2000–2002) they provided consensus guidelines on the use of radiotherapy [15Seegenschmiedt M.H. Katalinic A. Makoski H.-B. et al.Radiation therapy for benign diseases: patterns of care study in Germany.Int J Radiat Oncol Biol Phys. 2000; 47: 195-201Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 16Micke O. Seegenschmiedt MH for the German Working Group of Radiotherapy of Benign Diseases. Consensus guidelines for radiation therapy of benign diseases: a multicentre approach in Germany.Int J Radiat Oncol Biol Phys. 2002; 52: 496-513Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar], informed consent, treatment documentation and follow-up, including late toxicity scoring. A European Society for Radiotherapy and Oncology workshop in 2004 also reviewed the use of radiotherapy for benign disease and a consensus summary was published [[17]Leer J.W. van Houtte P. Seegenschmiedt H. Radiotherapy of non-malignant disorders: where do we stand?.Radiother Oncol. 2007; 83: 175-177Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar]. As with treating cancer, an overarching principle that also applies when treating benign disease is to minimise the volume of irradiated normal tissue. Current radiotherapy techniques can help to achieve this. For instance, modern imaging can allow more accurate target definition and other developments in immobilisation and image guidance can allow reduced margins. Techniques such as intensity-modulated radiotherapy, can achieve better conformality to complex target volumes, although this may increase the volume of tissue receiving lower doses. In some sites, particularly the skull base, dose distributions achievable with proton therapy may have advantages. It is important to note that there are currently only limited data regarding the application of modern radiotherapy techniques to the treatment of benign conditions, including the implications for RIC risks from treatments such as intensity-modulated radiotherapy. Much of the evidence reviewed is derived from radiotherapeutic literature, and it is frequently difficult to be certain as to how the use of radiotherapy would fit into the overall multimodality management of these conditions. It is hoped that this new review will lead to a reappraisal of the role of radiotherapy for benign conditions. It is recommended that there should be discussion at national and local levels between clinical oncologists and representatives of other professional bodies that often provide the primary consultants for these disparate conditions, e.g. ophthalmologists, orthopaedic surgeons, neurologists, dermatologists and urologists. It is recommended that radiotherapy departments should review their protocols for the treatment of benign diseases, including, where appropriate, the use of modern techniques. In view of the ageing population it is possible that radiotherapy could provide a useful treatment modality, with low toxicity, for patients with a range of benign conditions in an age group where the risk of RIC is not clinically relevant. Even in younger patients the benefits versus risk may be acceptable. It is hoped that the disease-specific information contained in the document will assist clinicians in the consent process, in particular advising patients on the balance between risks and benefits. In England there should be discussion within the Radiotherapy and Stereotactic Radiotherapy Clinical Reference Groups and the relevant commissioning organisations in Scotland, Wales and Northern Ireland regarding potential national approaches. We would like to thank Mrs Gillian Dollamore for co-ordinating the project, members of the Faculty Board of the Royal College of Radiologists Clinical Oncology Faculty for reviewing the manuscript and for helpful suggestions and the production team of the Royal College of Radiologists for production of the document to which this editorial refers.

Background This planning study compared Rapid Arc fixed field IMRT (cIMRT) 3D conformal radiotherapy (3D CRT), and a parallel opposed pair (POP) for children with retroperitoneal tumors Procedure Plans were generated in eight patients to treat the PTV (dose range 19 8-45 Gy) while limiting kidney and liver doses In selected patients vertebral body (VB) dose heterogeneity was minimized Cumulative DVH parameters, monitor units (MU) and treatment times were compared for the four techniques using the Wilcoxon matched pairs test Results RapidArc and cIMRT covered target volumes more conformally than 3D CRT and POP (P=0 012) There was no difference in the ability to meet kidney dose constraints A significantly lower volume of the liver received 12 Gy with cIMRT or RapidArc compared with 3D CRT (P=0 028) Where VB was included in PTV VB dose homogeneity was generally within 94-104% of the prescription dose Time to deliver a single fraction with RapidArc POP, 3D CRT, and cIMRT was 1 25 +/- 0 01, 1 38 +/- 0 10 2 6 +/- 0 45, and 4 02 +/- 1 12 min, respectively (P = 0 012) Monitor units for a single fraction with POP 3D CRT RapidArc, and cIMRT were 203 +/- 26, 235 +/- 32 325 +/- 71 and 665 +/- 215, respectively (P < 0 05) Conclusions POP resulted in favorable MU, treatment time and dosimetry but had poor conformality 3D CRT was more conformal but had higher MU and treatment time RapidArc and cIMRT were generally no better dosimetrically than conformal techniques RapidArc was dosimetrically very similar to cIMRT, but resulted in a major reduction in time and MU used to deliver the radiation Pediatr Blood Cancer 2011 56 16-23 (C) 2010 Wiley Liss Inc

In regard to Richard Shaffer et al.

Purpose: Volumetric modulated arc therapy (VMAT) is a novel extension of conventional intensity-modulated radiotherapy (cIMRT), in which an optimized three-dimensional dose distribution may be delivered in a single gantry rotation. VMAT is the predecessor to RapidArc (Varian Medical System). This study compared VMAT with cIMRT and with conventional modified wide-tangent (MWT) techniques for locoregional radiotherapy for left-sided breast cancer, including internal mammary nodes.Methods and Materials: Therapy for 5 patients previously treated with 50 Gy/25 fractions using nine-field cIMRT was replanned with VMAT and MWT. Comparative endpoints were planning target volume (PTV) dose homogeneity, doses to surrounding structures, number of monitor units, and treatment delivery time.Results: For VMAT, two 190 degrees arcs with 2-cm overlapping jaws were required to optimize over the large treatment volumes. Treatment plans generated using VMAT optimization resulted in PTV homogeneity similar to that of cIMRT and MWT. The average heart volumes receiving >30 Gy for VMAT, cIMRT, and MWT were 2.6% +/- 0.7%, 3.5% +/- 0.8%, and 16.4% +/- 4.3%, respectively, and the average ipsilateral lung volumes receiving >20 Gy were 16.9% +/- 1.1%, 17.3% +/- 0.9%, and 37.3% +/- 7.2%, respectively. The average mean dose to the contralateral medial breast was 3.2 +/- 0.6 Gy for VMAT, 4.3 +/- 0.4 Gy for cIMRT, and 4.4 +/- 4.7 Gy for MWT. The healthy tissue volume percentages receiving 5 Gy were significantly larger with VMAT (33.1% +/- 2.1%) and IMRT (45.3% +/- 3.1%) than with MWT (19.4% +/- 3.7%). VMAT reduced the number of monitor units by 30% and the treatment time by 55% compared with cIMRT.Conclusions: VMAT achieved similar PTV coverage and sparing of organs at risk, with fewer monitor units and shorter delivery time than cIMRT. Crown Copyright (C) 2010 Elsevier Inc.

PURPOSE:Volumetric modulated arc therapy (VMAT), the predecessor to Varian's RapidArc, is a novel extension of intensity-modulated radiotherapy (IMRT) wherein the dose is delivered in a single gantry rotation while the multileaf collimator leaves are in motion. Leaf positions and the weights of field samples along the arc are directly optimized, and a variable dose rate is used. This planning study compared seven-field coplanar IMRT (cIMRT) with VMAT for high-grade gliomas that had planning target volumes (PTVs) overlapping organs at risk (OARs). METHODS AND MATERIALS:10 previously treated patients were replanned to 60 Gy in 30 fractions with cIMRT and VMAT using the following planning objectives: 98% of PTV covered by 95% isodose without violating OAR and hotspot dose constraints. Mean OAR doses were maximally decreased without reducing PTV coverage or violating hotspot constraints. We compared dose-volume histogram data, monitor units, and treatment times. RESULTS:There was equivalent PTV coverage, homogeneity, and conformality. VMAT significantly reduced maximum and mean retinal, lens, and contralateral optic nerve doses compared with IMRT (p < 0.05). Brainstem, chiasm, and ipsilateral optic nerve doses were similar. For 2-Gy fractions, mean monitor units were as follows: cIMRT = 789 +/- 112 and VMAT = 363 +/- 45 (relative reduction 54%, p = 0.002), and mean treatment times (min) were as follows: cIMRT = 5.1 +/- 0.4 and VMAT = 1.8 +/- 0.1 (relative reduction 65%, p = 0.002). CONCLUSIONS:Compared with cIMRT, VMAT achieved equal or better PTV coverage and OAR sparing while using fewer monitor units and less time to treat high-grade gliomas.

PURPOSE:To examine the acute cardiotoxicity of internal mammary chain (IMC) irradiation with concurrent trastuzumab.MATERIALS AND METHODS:Clinical and cardiac function data were collected on 59 patients with early breast cancer who were treated with adjuvant trastuzumab and chemotherapy with or without radiotherapy (often including IMC) at BC Cancer Agency in 2005.RESULTS:Forty-four of fifty-nine patients received adjuvant radiotherapy (RT). Thirteen had left-sided IMC RT. For left-sided RT, IMC inclusion increased the mean percentage dose to 5% of the heart, but the mean doses to 50% and 90% of the heart were similar. Median baseline left ventricular ejection fraction (LVEF) was 62% and similar in all groups. Median absolute decrease in LVEF after RT was 4%, which was not significantly different according to side or inclusion of IMCs. Trastuzumab was stopped in 11 of 59 patients (18.6%) due to decrease in LVEF. After median follow up of 15 months, three patients developed clinical congestive heart failure, none of whom received left-sided IMC RT.CONCLUSIONS:There was no excess acute cardiotoxicity observed with the combination of left-sided IMC irradiation and concurrent trastuzumab.