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POST FORUM REPORT CONTENTS Dear Colleagues, I think we’ve finally cracked it! INTRODUCTION p3 2_ Delineation of organs-at-risk in the pelvic area: developing guidelines for RTTs p 28 CLINICAL p4 3_ Can O-MAR increase precision of delineation in Head and Neck Cancer? p 30 INTRODUCTION Overview of the Clinical & Translational Meeting Component p5 1_ A randomised controlled trial of Intensity Modulated Radiotherapy (IMRT) for early breast cancer: results at 5 years p6 2_ Recurrence pattern within the CROSS trials I and II, comparing surgery alone with chemoradiotherapy followed by surgery for esophageal cancer p7 3_ Development and validation of a prognostic model incorporating clinical and functional MRI variables in head and neck cancer p8 4_ A prospective study to compare doctor versus model predictions for outcome in lung cancer patients: pick the winner! p9 5_ Hypoxia biomarkers for prognostic evaluation and the prediction of outcome following prostate radiotherapy p 10 6_ Phase I/II Study of Palliative Radiation and Sorafenib for Metastatic Renal Cell Carcinoma and Bone Metastases p 12 PHYSICS p 14 INTRODUCTION Overview of the Biennial Physics Meeting Component p 15 1_ A National Dosimetric Audit of Volumetric Modulated Arc Therapy and Tomotherapy in the UK p 16 2_ Time dependent pre-treatment verification for VMAT plans using flattened or FFF beams p 18 3_ Validation of three deformable image registration algorithms using the TEST method p 20 4_ Kilovoltage intrafraction motion monitoring and target dose reconstruction for liver SBRT delivered by VMAT p 22 5_ An algorithm to assess the need for clinical Monte Carlo dose calculations for proton therapy fields p 23 RTT INTRODUCTION Overview of the RTT Meeting Component p 24 p 25 1_ A Planning Strategy for Generating a Library of Plans for Cervical Cancer p 26 2 CONTENTS | 2ND ESTRO FORUM - REPORT BRACHYTHERAPY INTRODUCTION Overview of the GEC-ESTRO-ISIORT Meeting Component p 32 p 33 1_ High Dose Rate (HDR) Brachytherapy Treatment Verification using an Electronic Portal Imaging Device (EPID) p 34 2_ HDR brachytherapy dosimetric predictors of biochemical control of prostate cancer p 36 3_ Dose-response for local control in image guided cervix brachytherapy in the retroEMBRACE study p 37 4_ Brachytherapy in the treatment of anal canal cancers: a large monocentric retrospective series. p 38 5_ HDR brachytherapy of the base of tongue. Ten-year results of a prospective study p 40 RADIOBIOLOGY INTRODUCTION Overview of the PREVENT Meeting Component p 42 p 43 1_ Second Cancer Risks after Radiotherapy for Breast Cancer: What is the Impact of Advanced Treatment Techniques? p 44 2_ LET dependent response of the rat cervical spinal cord after carbon ion irradiation p 45 3_ ACE-inhibition reduces acute cardiac damage to ameliorate radiation-induced lung dysfunction p 46 AWARDS p 48 INTRODUCTION p 49 1_ ESTRO - Varian Award p 50 2_ ESTRO - Accuray Award p 52 3_ ESTRO - Nucletron Brachytherapy Award p 54 4_ ESTRO - Jack Fowler University of Wisconsin Award 2013 p 56 5_ GEC-ESTRO Best Junior Presentation Sponsored by Nucletron p 58 This 2nd ESTRO Forum, hosted in Geneva, Switzerland in April, was a tremendous success and a feat that I think we can all be proud of from several different perspectives. The very positive feedback we received from delegates, speakers, partnering societies, exhibitors and industry partners proves that we are on the right track with our meeting, and this gives us exciting prospects for further consolidating the ESTRO Forum format in the future. The event can in effect be considered as a homage to radiation oncology itself, whereby all aspects of the field are covered and whereby interdisciplinarity and collegiality between all involved professionals are omnipresent. This Forum represented our second trial run – the first being the London Anniversary Meeting in 2011 – of a combined meeting format. We once again brought together the clinical & translational meeting, the GEC-ESTRO-ISIORT meeting, the Physics biennial meeting, the RTT meeting, and the PreVent (Prediction, recognition, eValuation and eradication of normal tissue effects of radiotherapy) meeting. The joining of forces has resulted in a ‘tour de force’ when considering the scientic programme that was put before you. The scientific experts of the five meetings did an outstanding job that culminated in a programme of interest for clinicians, medical physicists, biologists, radiation technologists, nurses, and anyone with an interest in the field of radiation oncology. Moreover, the younger professionals were also specifically catered for with dedicated sessions. This programme could not have been presented to you without all those fine abstracts that were sent to us. Here in this report each Scientific Committee Chair has made a selection of those that they wish to further bring into the limelight; we have compiled these noteworthy abstracts, as well as certain Award abstracts, for you in this report. I would also like to present you with some numbers that stand testament to the solid basis of the ESTRO Forum format. For the forum in Geneva we had: 3647 delegates in total Attendees from 67 countries, with 78% coming from Europe. Physicists and radiation oncologists each made up 37% of the attendees, followed by RTTs (14%) and clinicians (5%) A total of 161 sessions, of which 26 were interdisciplinary 1175 abstracts were received 335 abstracts selected for oral and poster presentations 260 invited speakers 88 exhibiting companies demonstrated their wares and know-how 121 persons attending the contouring workshops 438 persons attending the 6 pre-conference courses 10 commercial satellite symposia hosted Now that we know we’ve cracked it, we can continue along this organisational course and host future congresses that we know for sure will appeal to you…and together persevere with our efforts of developing optimal patient care and equitable access to cutting-edge radiation therapy. Vincenzo Valentini President of ESTRO 2ND ESTRO FORUM - REPORT | INTRODUCTION 3 CLINICAL Introduction OVERVIEW OF THE CLINICAL & TRANSLATIONAL MEETING COMPONENT p5 1_ A RANDOMISED CONTROLLED TRIAL OF INTENSITY MODULATED RADIOTHERAPY (IMRT) FOR EARLY BREAST CANCER: RESULTS AT 5 YEARS p6 2_ RECURRENCE PATTERN WITHIN THE CROSS TRIALS I AND II, COMPARING SURGERY ALONE WITH CHEMORADIOTHERAPY FOLLOWED BY SURGERY FOR ESOPHAGEAL CANCER p7 3_ DEVELOPMENT AND VALIDATION OF A PROGNOSTIC MODEL INCORPORATING CLINICAL AND FUNCTIONAL MRI VARIABLES IN HEAD AND NECK CANCER p8 4_ A PROSPECTIVE STUDY TO COMPARE DOCTOR VERSUS MODEL PREDICTIONS FOR OUTCOME IN LUNG CANCER PATIENTS: PICK THE WINNER! 5_ HYPOXIA BIOMARKERS FOR PROGNOSTIC EVALUATION AND THE PREDICTION OF OUTCOME FOLLOWING PROSTATE RADIOTHERAPY 6_ PHASE I/II STUDY OF PALLIATIVE RADIATION AND SORAFENIB FOR METASTATIC RENAL CELL CARCINOMA AND BONE METASTASES p9 p 10 p 12 OVERVIEW OF THE CLINICAL & TRANSLATIONAL MEETING COMPONENT based approach seems relevant as well as promising to predict both treatment response and toxicity. In the past decennium, and pointing onwards to the immediate future, clinical radiotherapy has undergone considerable developments, essentially including technological advances in radiation delivery, the demonstration of the benefit of adding concomitant cytotoxic agents to radiotherapy for a range of tumour types and the increasing integration of targeted therapeutics for biological optimisation of radiation effects. Within this frame of reference, the Clinical & Translation Meeting of the 2nd ESTRO Forum highlighted a number of important study breakthroughs, which were reported in meeting abstracts that I have had the privilege to summarise in this overview. The abstract with the appealing title ‘A prospective study to compare doctor versus model predictions for outcome in lung cancer patients: pick the winner!’ by Oberije et al. presented data that many of us, in our role as clinicians, may regard as somewhat provocative. For lung cancer patients receiving definitive radiotherapy, applying a prospective study design to compare the physicians’ ability to predict patient survival and treatment toxicity with the accuracy of a prediction model based on patient, tumour and treatment characteristics, showed that the doctors’ clinical foresight was inferior to that of the model! Two of the abstracts, in particular, epitomised classic randomised clinical trials of treatment response and toxicity outcome, but at the same time reported on new or controversial topics. The abstract entitled ‘A randomised controlled trial of Intensity Modulated Radiotherapy (IMRT) for early breast cancer: results at 5 years’ by Coles et al. reported on the randomisation of more than 800 breast cancer patients between intensity modulated radiotherapy (IMRT) and two-dimensional breast radiotherapy (2DRT). As the largest prospective trial in the world so far to test breast IMRT against 2DRT, this study demonstrated that the former translated into superior overall long-term side effects, and also embodied this aspect as an important outcome parameter in modern radiotherapy trials. The other abstract specifically attracting my attention was the one entitled ‘Effect of preoperative chemoradiotherapy on recurrence pattern in esophageal tumors’ by the Dutch multi-centre CROSS I and II trials group. Study patients with oesophageal carcinoma were randomised between chemoradiotherapy (CRT) followed by surgery and surgery alone. The CRT plus surgery approach improved local recurrence outcome, and also decreased the rate of systemic disease recurrence, suggesting a change in the standard of care of this disease to take into account the general biological effects of what has been thought of as treatment to control local disease. Biological modelling is increasingly important in clinical radiotherapy, and I looked with great interest at a number of studies applying the promising opportunities of such approaches. Of these I will highlight two in particular. The abstract ‘Development of a predictive model incorporating clinical and functional MRI variables in head and neck cancer’ by Lambrecht et al. described the correlation of functional magnetic resonance imaging (MRI) tumour data with disease free survival in head-and-neck cancer patients after CRT. Additionally, this functional MRI data was used to develop a prognostic model, which at this stage needs more statistical evaluation; however, this biologically 4 CLINICAL | 2ND ESTRO FORUM - REPORT From a clinical perspective, as knowledge accumulates from molecular radiobiology, there is a complex and exciting opportunity for rational patient treatment stratification in radiotherapy. Within this context, a number of novel studies were reported, from which with difficulty I had to select two to highlight here. In the study ‘Hypoxia biomarkers for prognostic evaluation and the prediction of outcome following prostate radiotherapy’, Alonzi et al. had analysed three hypoxia biomarkers in tumour biopsy samples from almost 200 patients that had been enrolled in a trial comparing conventional versus high-dose radiotherapy for prostate cancer. The investigators showed that tumour expression of the biomarkers was associated with shorter recurrence-free survival following radiotherapy and, for tumours expressing one of the biomarkers, that there was a significant patient benefit of radiation dose escalation. Finally, in the ‘Phase I/II Study of Palliative Radiation and Sorafenib for Metastatic Renal Cell Carcinoma and Bone Metastases’, Han et al. had used sorafenib, an anti-angiogenic, multi-targeted tyrosine kinase inhibitor, in combination with palliative radiation of painful bone metastases in renal cell carcinoma patients. In line with preclinical evidence of a radiosensitising activity of sorafenib, the investigators demonstrated both symptomatic and radiographic treatment response (pain relief and reduced target lesion metabolic activity, respectively), while there were no severe adverse effects reported from the combined-modality therapy. The 2nd ESTRO Forum Clinical & Translational Meeting provided a combination of translational science, proof-of-principle early clinical studies and randomised controlled clinical trials, enabling radiation oncology to continue to position itself with the highest level of evidence within existing clinical practice. The selected studies referenced above strongly manifest the principal vision of the ESTRO 2012 Strategy Document on the development of the discipline within future cancer care. Anne Hansen Ree Member of the Clinical & Interdisciplinary Meeting Committee In collaboration with Donal Hollywood (†), Chair of the meeting 2ND ESTRO FORUM - REPORT | CLINICAL 5 1 2 A RANDOMISED CONTROLLED TRIAL OF INTENSITY MODULATED RADIOTHERAPY (IMRT) FOR EARLY BREAST CANCER: RESULTS AT 5 YEARS By Dr Charlotte Coles Cambridge University Hospitals NHS Foundation Trust, UK RECURRENCE PATTERN WITHIN THE CROSS TRIALS I AND II, COMPARING SURGERY ALONE WITH CHEMORADIOTHERAPY FOLLOWED BY SURGERY FOR ESOPHAGEAL CANCER By MCCM Hulshof Academic Medical Center, Amsterdam, The Netherlands CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Uneven radiotherapy dose can cause changes to the normal breast tissue, which can result in a poorer cosmetic appearance months and years after completion of treatment. A poor cosmetic outcome from treatment of primary breast cancer has been shown to adversely affect patient’s psychosocial well-being. Intensity Modulated Radiotherapy (IMRT) is a radiation technique, which enables an even dose to be given across the breast, but is more time consuming and requires more resources than standard two-dimensional breast radiotherapy (2DRT). The aim of this randomised trial was to investigate whether IMRT reduces toxicity to breast tissue and produces a better appearance at 5 years from completion of treatment. ABSTRACT OVERVIEW: Intensity Modulated Radiotherapy (IMRT) is a radiation technique, which enables an even dose to be given across the breast. The aim of this large randomised trial was to investigate whether IMRT reduces toxicity to breast tissue and produces a better appearance at 5 years after treatment compared with two-dimensional breast radiotherapy (2DRT). Treatment plans of 1145 patients with early breast cancer were analysed to see if they would produce an uneven radiation dose with 2DRT. 71% of the plans fell into this category, and those patients were randomised between standard 2DRT and IMRT. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? This study is unique as it is the largest prospective trial in the world to test breast IMRT against 2DRT. The three main findings at 5 years after completion of breast treatment are: 1. IMRT produces a better cosmetic breast appearance 2. IMRT reduces the risk of skin telangiectasia (dilated blood vessels near the surface of the skin) 3. The surgical cosmesis should be optimised as this also has a significant effect on late breast toxicities 6 CLINICAL | 2ND ESTRO FORUM - REPORT WHAT IMPACT COULD YOUR RESEARCH HAVE? The researchers intend to follow up their work by analysing the patients’ questionnaires to see whether IMRT has an influence on quality of life. The trial has also contributed 1000 blood samples to the UK translational research study RAPPER (Radiogenomics: Assessment of Polymorphisms for Predicting the Effects of Radiotherapy), which ultimately aims to develop individualised radiotherapy plans based on analysis of patient’s unique genetic make up. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Although IMRT is employed increasingly in breast cancer, its use is far from universal throughout the world. We hope that the evidence of benefit shown in our trial will encourage its greater use, resulting in improved patient access and, ultimately, improved outcomes for breast cancer patients. CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Preoperative chemo radiotherapy (CRT) followed by surgery for patients with esophageal carcinoma has demonstrated to improve overall and disease free survival compared to surgery alone. The context of the study is to analyse the exact effect of preoperative CRT on site and rate of tumour recurrences, based on a randomised study. ABSTRACT OVERVIEW : To analyze the difference in recurrence pattern for patients with esophageal or gastro-esophageal carcinoma between treatment with surgery alone versus preoperative chemo radiotherapy followed by surgery, using a dose of 41,4 Gy plus concurrent weekly paclitaxel and carboplatin, What were the three main findings of your research? After a minimum follow-up of 24 months 58% patients had a recurrence after surgery alone and 35% after CRT + surgery. CRT reduced the locoregional recurrences from 36% to 13%. Peritoneal carcinomatosis occurred in 14% after surgery alone versus 4% after CRT + Surgery. Loco regional recurrences occurred within the radiation field in 5% of the patients, borderline in 2%, out-field in 6% and unclear in 1%. The majority of loco regional recurrences had concurrent distal failures. Figure: Locoregional recurrence free survival; recurrences at anastomotic site and/or in mediastinal, celiac trunk or supraclavicular lymph nodes. P<0.0001. Arm 0 = preoperative CRT + surgery, arm 1 = surgery alone WHAT IMPACT COULD YOUR RESEARCH HAVE? Preoperative CRT has impact on survival by reducing the loco regional recurrences rate and by reducing peritoneal seeding. Some further improvement in loco regional recurrence rate can be achieved by extending the radiation fields and improving treatment accuracy, although a large effect on survival is not expected IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? The study confirms that a moderate preoperative radiation dose combined with mild concurrent chemotherapy improves survival by improving the locoregional tumor control rate. It further suggests that pre operative CRT reduces peritoneal seeding by reducing peroperative tumorspill in the abdomen 2ND ESTRO FORUM - REPORT | CLINICAL 7 3 4 DEVELOPMENT AND VALIDATION OF A PROGNOSTIC MODEL INCORPORATING CLINICAL AND FUNCTIONAL MRI VARIABLES IN HEAD AND NECK CANCER A PROSPECTIVE STUDY TO COMPARE DOCTOR VERSUS MODEL PREDICTIONS FOR OUTCOME IN LUNG CANCER PATIENTS: PICK THE WINNER! By Lambrecht Maarten, MD MAASTRO Clinic, Maastricht, The Netherlands By Cary Oberije Department of Radiation Oncology, University Hospitals Gasthuisberg, UZ Leuven, Leuven, Belgium CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Diffusion weighted imaging (DWI) is a functional MRI technique which allows us to characterize tissues based on the mobility of water protons. This information can be quantified and visualized and thus provides us with valuable insight in the tumor’s microstructure. ABSTRACT OVERVIEW: The main purpose was to investigate whether DWI has a prognostic value for disease free survival (DFS) in head and neck cancer patients treated with (chemo-) radiotherapy. Secondly we wanted to develop a prognostic model incorporating clinical, anatomical and DWI parameters, which could be helpful in patient selection, based on their expected response, prior to treatment. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? After multivariate analysis we found that the pretreatment ADC value, derived from high b-values was a significant prognostic factor in head and neck cancer patients treated with (chemo-) radiotherapy (for DFS, HR 1.14; 95%CI 1.04-1.25; p:0.005) . The resulting prognostic model was able to differentiate poor responders from good responders (3 year DFS: 44% in poor responders vs 67% and 69% for the intermediate and good responders respectively). This information was put into a nomogram (Figure 1) correlating all relevant parameters to DFS probability. Although promising, the performance of the model is still suboptimal and requires further improvement (c-index:0.62). The addition of biological, molecular and genetic information might further increase its performance. in biological, molecular and genetic factors. The ability to identify these factors, would enable us to select patients for treatment adaptation beforehand, potentially increasing tumor control while reducing therapy related morbidity for the entire population. Non-invasive functional imaging technique can be a very useful asset in this respect. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Up to now treatment in many cancer sites is based on histological and anatomical findings. However, it is becoming increasingly clear that while these tumors might be identical in basic anatomy and histology, their response to standard treatment differs greatly. This heterogeneity suggests that a more patient tailored treatment approach is essential if we want to further improve our results both for tumor control and treatment related toxicity. However, there are many factors which potentially play a role in the response of a tumor to treatment, making evidence-based clinical interpretation a nearly impossible task. Therefore solid statistical analysis is essential to assess the true value of all different factors and integrate them into an evidence-based and robust clinical decision model. CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: The number of treatment options available for lung cancer patients are increasing, as well as the amount of information available for an individual patient (genomics, proteomics, radiomics). Doctors have to choose the optimal treatment option for an individual patient by combining all this information, but this is a difficult task for humans. However, prediction models can incorporate and combine this information and thus offer assistance in clinical decision making. ABSTRACT OVERVIEW: Models for lung cancer patients to predict treatment-induced dysphagia (difficulty with swallowing), dyspnea (shortness of breath) and survival were already developed and tested. We hypothesized that these models would outperform the doctors’ predictions. Experienced radiation oncologists were asked to predict 2 year survival, dyspnea and dysphagia at two time points: 1) after they had seen a patient for the first visit, and 2) after the treatment plan was made. Patient, tumor and treatment characteristics were used by the models to calculate the probability for each outcome. We compared the performance of models to doctors’ in terms of AUC. An AUC of 1 indicates a perfect prediction while an AUC of 0.5 is as good as chance (tossing a coin). WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? Prediction models for lung cancer patients substantially outperformed the physicians’ prediction for all outcomes. The difference between doctors and models did not decrease after the doctors had seen the patient or the treatment planning. The models were especially superior in identifying high risk patients and should therefore be implemented in clinical practice to guide decisions. WHAT IMPACT COULD YOUR RESEARCH HAVE? By showing that models outperform radiation oncologists, we hope that more people are willing to use prediction models and to collect and exchange data to improve the existing models. This will eventually lead to optimal treatment decisions for individual patients. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? It becomes more and more evident that some patients benefit from a specific treatment while others don’t and some patients suffer from severe side-effects while others don’t. The amount of information to explain these findings is increasing (genomics, proteomics, radiomics). This will lead to an individualized treatment. In our opinion, individualized treatment can only succeed if prediction models are used in clinical practice. These models can combine many factors, while this is a difficult task for humans. If models, based on patient, tumor and treatment characteristics, already outperform the doctors, these results can be used as a strong argument in favour of using prediction models and changing current clinical practice. Eventually, in the future, it will be regarded as unethical to make treatment decisions based solely on doctors’ opinion. WHAT IMPACT COULD YOUR RESEARCH HAVE? Over the last decades the treatment of head and neck cancer has intensified and significantly improved both tumor control and overall survival rates. However, this has come at the cost of both acute and late toxicity, rendering further uniform treatment intensification impossible. Furthermore it is becoming increasingly clear that while these tumors can be identical in location and basic histology, their response to chemoradiotherapy (CRT) differs greatly. These differences in sensitivity can be explained by variations 8 CLINICAL | 2ND ESTRO FORUM - REPORT Figure 1: Nomogram correlating clinical and imaging variables to probability of disease free survival (DFS). Comparison of models’ versus radiation oncologists’ predictions. The surface or area below the plotted the line is used for measuring the accuracy of predictions, 1 represents a perfect prediction, while 0.5 represents predictions that were right in 50% of cases, i.e. the same as chance. 2ND ESTRO FORUM - REPORT | CLINICAL 9 5 HYPOXIA BIOMARKERS FOR PROGNOSTIC EVALUATION AND THE PREDICTION OF OUTCOME FOLLOWING PROSTATE RADIOTHERAPY By Roberto Alonzi Mount Vernon Cancer Centre, UK CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Radiotherapy is commonly used as a curative treatment for prostate cancer. We now understand that the higher the radiation dose administered to a prostate cancer, the greater the chance of long-term tumour control. This increased dose inevitably results in greater normal tissue toxicity. However, even before the use of modern high-dose radiotherapy for prostate cancer, a proportion of patients was cured using the ‘conventional’ doses prescribed at that time. If we were able to detect in advance which patients actually need the higher radiation dose and which men could be safely treated with lower doses, then a significant number of men would be spared the toxicity of dose-escalated radiation therapy. Prostate cancers frequently contain regions of low oxygenation. We have known for a long time that hypoxic tumours require a higher radiation dose than non-hypoxic tumours to provide an equivalent level of control. It is therefore possible that hypoxia biomarkers may predict which men specifically require high dose radiotherapy. ABSTRACT OVERVIEW: In this research we analysed the prostate biopsy samples of 191 men who were enrolled in a trial that compared conventional versus high dose radiotherapy for prostate cancer. Three immunohistochemical biomarkers of tumour hypoxia were evaluated for each patient (Glut1, HIF1α and Osteopontin) using monoclonal antibodies. Tumours were assessed for biomarker expression by two independent investigators, blinded to patient outcome and scored as negative or positive depending on the proportion of cells staining for the marker in question. The relapse free interval for all patients was then determined using the Kaplan-Meier method. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? 1. Expression of any of the three hypoxia biomarkers confers a poorer prognosis for patients receiving prostate radiotherapy compared to those that do not express these biomarkers. For Glut1, HIF1α and Osteopontin respectively there was a 20.2 (p=0.005), 23.0 (p=0.019) and 22.5 (p=0.012) month reduction in mean relapse free interval associated with biomarker expression. 10 CLINICAL | 2ND ESTRO FORUM - REPORT 2. Osteopontin expression predicted a need for radiotherapy dose escalation. In patients without osteopontin expression there was no benefit from the administration of a high radiation dose (p=0.349), whereas for those men whose biopsy samples expressed osteopontin, there was a significant benefit from dose escalation (p=0.017). However, the converse was true for Glut1 with negative expression predicting a benefit for dose escalation (p=0.006), (figure 1). 3. These results generate the following hypothesis: osteopontin becomes positive in the presence of mild/moderate hypoxia, whereas Glut1 only becomes positive under conditions of severe hypoxia. Therefore, If both osteopontin and Glut1 are negative (i.e. minimal hypoxia), there is no benefit from dose escalation. If osteopontin is positive and Glut1 is negative (moderate hypoxia), there is a benefit for dose escalation. However, If Glut1 is positive (severe hypoxia), there is no benefit from dose escalation because patients will do badly despite very high doses of radiotherapy. This hypothesis is supported by the fact that the Glut1 positive men (regardless of the expression of the other markers) had the poorest median relapse free interval of all, (figure 2). of those who receive them. Better predictive markers are urgently required to direct treatments to those who will actually benefit from them. This will spare many patients from unnecessary side effects and free resources for more effective use. Figure 1. Kaplan-Meier survival curves for each of the hypoxia biomarkers, each showing that expression of any of the three hypoxia biomarkers confers a poorer prognosis for patients receiving prostate radiotherapy compared to those that do not express these biomarkers. WHAT IMPACT COULD YOUR RESEARCH HAVE? The above hypothesis is currently being tested using an independent dataset. If confirmed, these results could cause a significant change in clinical practice. Firstly, men with non-hypoxic tumours (i.e. Glut1 negative and osteopontin negative) could be spared the toxicity of high dose radiotherapy. Secondly, men with moderate tumour hypoxia would be identified and given the opportunity to receive high-dose radiation. Thirdly, those with severely hypoxic tumours (Glut1 positive) may need to consider an alternative treatment option such as surgery or alternatively be enrolled into a clinical trial of radiotherapy in conjunction with hypoxia modification (as in the PROCON study, UK) IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Biomarker-guided therapy is currently a focus of intense research in many tumour types. Most cancer therapies are toxic and only result in an advantage for a proportion Figure 2. Kaplan-Meier survival curves for each hypoxia category. Blue = minimal hypoxia (Glut1 negative and osteopontin negative), green = moderate hypoxia (Glut1 negative and osteopontin positive) and yellow = sever hypoxia (Glut1 positive and osteopontin positive). The test equality of survival distributions for the different hypoxia categories demonstrates significance (p=0.004). 2ND ESTRO FORUM - REPORT | CLINICAL 11 6 PHASE I/II STUDY OF PALLIATIVE RADIATION AND SORAFENIB FOR METASTATIC RENAL CELL CARCINOMA AND BONE METASTASES By Kathy Han Princess Margaret Cancer Centre, Canada CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Bone metastases from renal cell carcinoma (RCC) are common and often less responsive to palliative radiotherapy (RT) than metastases from other tumors. Sorafenib is a multi-targeted tyrosine-kinase inhibitor that inhibits angiogenesis, and has been shown to improve progression-free survival as a mono-agent in metastatic RCC in clinical trials. There is pre-clinical evidence to indicate that inhibition of angiogenesis with sorafenib can improve the effectiveness of RT. The purpose of this study was to examine the efficacy and toxicity of sorafenib in patients with RCC receiving palliative RT for painful bone metastases. ABSTRACT OVERVIEW: Objectives: 1. Determine the pain response to a combination of palliative RT and sorafenib in patients with RCC and symptomatic bony metastases. 2. Determine the toxicity of palliative RT and sorafenib. 3. Determine preliminary biological activity of RT and sorafenib from PET-CT scan results before and after treatment. 4. Obtain preliminary information about the effect of RT and sorafenib on disease control, as measured by clinical or radiographic evidence of disease progression at the treated site, the need for subsequent RT or the need for other interventions because of progression at the treated site. WHAT IMPACT COULD YOUR RESEARCH HAVE? Given that the combination of RT and sorafenib did not result in severe side effects directly, and provided good pain relief and radiographic response in this study, sorafenib and palliative RT show promise as a combined modality treatment for metastatic RCC. This study provides a treatment schema for RT and sorafenib to be tested in a larger clinical trial for safety and efficacy. Fused PET-CT images at (a) baseline and (b) 7 weeks (4 weeks after completing radiotherapy) showing lower FDG uptake in the target lesion at 7 weeks (Figure 1) but higher uptake in a non-target lesion at 7 weeks (Figure 2). Figure 1 (a) Figure 2 (a) Figure 1 (b) Figure 2 (b) IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? There is increasing interest in combining RT with molecularly targeted agents to improve radiation response. Sorafenib, an oral multi-targeted tyrosine kinase inhibitor that has been shown to prolong progression-free survival in patients with metastatic RCC, is a standard treatment option for metastatic RCC. There is emerging evidence that sorafenib has synergistic effects with radiation in preclinical studies. To our knowledge, this is the first clinical study to investigate the efficacy and toxicity of combining sorafenib and palliative RT for the treatment of symptomatic bony metastasis in patients with RCC. The number of studies investigating the efficacy of sorafenib in combination with RT for other cancers is rising. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? Mean ‘present’ pain scores at baseline, 7 weeks and 12 weeks were 3.9, 1.6, and 1.6, respectively (p=0.04). Only two patients required re-irradiation of a previously treated index lesion. Seven other patients required subsequent RT for symptomatic progression of previously untreated lesions. 1. There were no severe side effects directly attributable to the combination of RT and sorafenib. 2. There was a significant difference in the metabolic response of target lesions versus non-target lesions (p=0.002). For target lesions, SUV decreased (5.4 to 3.9) after RT and sorafenib (p=0.003). However, for non-target lesions, there was a trend towards an increase in SUV (3.9 to 5.0) (p=0.08). 12 CLINICAL | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | CLINICAL 13 PHYSICS OVERVIEW OF THE BIENNIAL PHYSICS MEETING COMPONENT The physics abstracts highlighted here represent a selection of the very best proffered papers presented at the 12th edition of ESTRO’s Biennial Physics Conference. These abstracts have been selected as they provide important guidance for both the current and future practice of radiotherapy, underlining the key role of medical physics for both scientific and clinical progress in this field. Introduction OVERVIEW OF THE BIENNIAL PHYSICS MEETING COMPONENT p 15 1_ A NATIONAL DOSIMETRIC AUDIT OF VOLUMETRIC MODULATED ARC THERAPY AND TOMOTHERAPY IN THE UK p 16 2_ TIME DEPENDENT PRE-TREATMENT VERIFICATION FOR VMAT PLANS USING FLATTENED OR FFF BEAMS p 18 3_ VALIDATION OF THREE DEFORMABLE IMAGE REGISTRATION ALGORITHMS USING THE TEST METHOD One of the abstracts (Clark et al.) describes the findings of the first detector array based dosimetry audit for rotational IMRT, which was performed on a nationwide basis in the UK. The importance of this study is that it demonstrates that a treatment modality of such high complexity can be safely implemented on a widespread basis. A second abstract (Podesta et al.) also deals with dosimetric verification of rotational IMRT. This study more specifically addressed the temporal aspect of the delivery and dosimetry process, presenting a new method that allows for verification of each portion of the complex delivery course of a rotational IMRT fraction, rather than the total integrated beam delivery verification used in current approaches. Another highlighted abstract (Wittendorp et al.) presents a new method to validate deformable image registration algorithms, a key tool for a number of image-guided and adaptive radiotherapy applications. The method combines several features of the registration, giving a more complete characterization of the registration quality. The method is likely to become a very useful instrument in the implementation process of adaptive radiotherapy. Finally, the two last selected abstracts present studies related to upcoming RT delivery techniques: real-time monitoring/ tracking of tumours (Poulsen et al.) and proton therapy (Bueno et al.). The Poulsen study specifically presents a new method to calculate the dose actually received in moving targets using CBCT-based target trajectory estimation, providing a widely accessible tool to evaluate the consequences of intra-fractional motion in terms of target dose distributions. The Bueno study focuses on the challenges of treatment planning calculations for protons, and in particular developed a measure – based on the degree of density heterogeneity lateral to the beam – that indicates when the more time-consuming Monte Carlo calculations are required instead of the conventional pencil beam algorithm. Make sure to read the very interesting physics abstract featured in the Awards section of this report. p 20 Ludvig Paul Muren 14 Chair of the Biennial Physics Meeting 4_ KILOVOLTAGE INTRAFRACTION MOTION MONITORING AND TARGET DOSE RECONSTRUCTION FOR LIVER SBRT DELIVERED BY VMAT p 22 5_ AN ALGORITHM TO ASSESS THE NEED FOR CLINICAL MONTE CARLO DOSE CALCULATIONS FOR PROTON THERAPY FIELDS p 23 PHYSICS | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | PHYSICS 15 1 A NATIONAL DOSIMETRIC AUDIT OF VOLUMETRIC MODULATED ARC THERAPY AND TOMOTHERAPY IN THE UK By Catharine Clark Royal Surrey County Hospital and National Physical Laboratory, UK CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Volumetric Modulated Arc Therapy (VMAT) and Tomotherapy (collectively named rotational radiotherapy (RRT)) have the capability to sculpt the radiotherapy dose to the shape of the tumour target and spare normal tissue. A survey of UK cancer centres in 2011 indicated that there was a rapid uptake of RRT (Varian RapidArc, Elekta VMAT or Helical Tomotherapy), and that by 2012, 50% of the centres would be offering this treatment. This highlighted the need for a national audit of dose measurement of RRT in order to ensure safe and accurate implementation. ABSTRACT OVERVIEW: We had previously investigated the use of a detector array system, which allows simultaneous measurement of dose at hundreds of points in a patient plan, for dosimetry audit and developed a methodology for comparison of calculated plans with measurement at plan delivery. The present work represented the performance and comparison of measurements across 30 centres in the UK. The results have shown that the majority of centres offering RRT are able to model the dose distribution and deliver the plans accurately both in terms of the dose to a point and the distribution of the dose. WHAT IMPACT COULD YOUR RESEARCH HAVE? This work has confirmed that centres are safely able to deliver the calculated plans generated for this advanced radiotherapy technique. It has also set standards for future centres in their implementation process. The collaborative nature of the audit with the national radiotherapy trials quality assurance team also meant that centres were certified to join a clinical trial using their rotational technique on successful completion of the audit. The methods developed for use of an array detector system could be used for other advanced radiotherapy techniques. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? This work is the first audit of VMAT and Tomotherapy to use a detector array system. As radiotherapy techniques become more complex, so the audit procedures which validate them need to develop to provide appropriate measurement approaches. The process of employment of advanced techniques benefits from external review and audit to ensure safe and accurate implementation. PTW 2D array used for measurements in each hospital WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? Centres were asked to create both a generic plan and a patient-specific clinical trial plan. Following measurement of the delivered plan with the array, differences between the calculated and delivered plans were investigated in two ways: (a) looking at specific points associated with individual target volumes and areas of avoidance and (b) using an index (gamma index) which gives a measure of how closely the delivered and calculated plans match in terms of dose distribution. The results showed that the dose at specific points for all plans gave a mean difference of less than 0.5% across the 30 centres. For the dose distributions, in 93% of all the measurements 95%of the measured plane matched within accepted criteria of 3% and 3mm. The 3DTPS plan which all hospitals planned and delivered, measured in two coronal planes and one sagittal plane 16 PHYSICS | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | PHYSICS 17 2 TIME DEPENDENT PRE-TREATMENT VERIFICATION FOR VMAT PLANS USING FLATTENED OR FFF BEAMS By Mark Podesta Maastro Clinic, The Netherlands CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: External beam treatments for radiotherapy require testing before they are performed on a patient to ensure the equipment and software performs as intended and to minimise the possible problems that can occur during patient therapy. While several solutions exist to perform these checks, arguably the method requiring the least amount of time and additional equipment, is to use the Electronic Portal Image Device (EPID), typically provided as standard on the equipment used to deliver external beam treatments. The EPID is akin to a digital camera for radiation and with proper calibration the EPID can be used to measure radiation dose. To date, pre-treatment verification uses EPID dosimetry in a long-exposure fashion, turning on the camera and accumulating the signal over the whole treatment. This allows each accumulated radiation field to be verified but does not verify the steps during the field which can be numerous and widely variant. We propose a method where the EPID can be used in more of a movie mode where each step of the planned treatment can be verified in small time intervals. ABSTRACT OVERVIEW: Portal dosimetry is a robust way to verify external beam therapies before the treatment is administered. Until now portal dosimetry has only been performed using integrated field images and typically using flattened beams. For fast, dynamic therapies such as VMAT, which can contain hundreds of field shapes, this may not be sufficient. For example, a VMAT fraction can be delivered in ~1-3 minutes using ~180 control points with varying field shapes and dose rates. These deliveries are much more dependent on equipment precision and accuracy when compared to static treatments. We think it necessary to verify these deliveries with added scrutiny and so we present a portal dosimetry method to verify VMAT plans in a time-dependent manner using flattened or unflattened beams. Doses delivered at a particular point in time may deviate from predicted doses, as shown by time-dependent verification. These errors are typically hidden in integrated field images. New action levels are required to indicate how much deviation during a treatment is permissible as current action levels are not immediately applicable. WHAT IMPACT COULD YOUR RESEARCH HAVE? The method described here will allow for a higher level of verification for currently implemented dynamic external beam therapies such as IMRT and VMAT. It will also provide added confidence for centres considering flattening filter free beams in their therapy options. Future work will include development of time-dependent 2D transit dosimetry and full 4D in-vivo dose reconstruction. Fig. 1. Continuous verification of a VMAT plan, deviation versus beam angle. Red and blue areas indicate over/under dose respectively. Fig. 2. Gamma distributions (3%, 3mm, 3sec) between measurement and prediction of 2D doses for a single VMAT 6MV FFF arc. Red and blue areas indicate over/under dose respectively. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Standardisation, reliability, consistency, and quality assurance are key aspects of modern complex radiation oncology which can appear to be in opposition to the other key aspect of patient specific treatment. EPID dosimetry and time-dependent EPID dosimetry in particular can standardize the verification of different external beam therapies. This can result in less variation in treatment consistency through inter-fractional adaptation, while still catching more day-of-delivery errors using correctly chosen action levels. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? We show time-dependent pre-treatment portal dose verification is possible, without the need of any additional equipment (detector or specialised phantom) and no additional set-up is required to include unflattened beams. 18 PHYSICS | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | PHYSICS 19 3 VALIDATION OF THREE DEFORMABLE IMAGE REGISTRATION ALGORITHMS USING THE TEST METHOD By Paul. W.H. Wittendorp University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, Groningen, The Netherlands CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: The anatomy of patients can change during radiotherapy treatment, which can last up to 7 weeks, For example, patients can lose weight or the tumour can change shape. The ability to map these and other changes in the patient allows the possibility of adapting the radiotherapy treatment. The changes can be mapped with deformable image registration (DIR). As DIR algorithms are still under development, it is essential to verify the accuracy of the calculated deformations. Methods currently used to quantify DIR accuracy often only provide information about image regions with high contrast (e.g. anatomical landmarks). However, in adaptive radiotherapty (ART) it is important to know the deformation accuracy in the entire irradiated volume. Therefore, we developed a method that quantifies the DIR accuracy both in high and low contrast regions in the image. ABSTRACT OVERVIEW: The objective of the current study was to determine which of three frequently used DIR algorithms (Demons, SFBR, and B-Spline) give the best performance, when used for the deformation from planning CT (pCT) to repeat CT (rCT) in patients treated for head and neck cancer. For this purpose we developed the TEST method which combines four different verification methods: 1) Target registration error, 2) expansion, 3) shear strain, and 4) transitivity. Using these multiple methods we were able to quantify the deformations in the high and low contrast regions and to determine whether the deformation was anatomically plausible, see figure 1. WHAT IMPACT COULD YOU RESEARCH HAVE? We showed that the TEST method can be used to compare the accuracy of different DIR algorithms. This quantitative method to verify the deformations can help compare the DIR accuracy in different radiotherapy departments or help a single department to choose the best DIR algorithm for their application. Furthermore, the TEST method gives quantitative information both in high and low contrast regions and gives information about the anatomical plausibility of deformation. This information is essential to determine whether a DIR result is accurate enough to use in an adaptive radiotherapy procedure. IS THE RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? All radiotherapy departments want to provide the best treatment to their patients. An increasing number of departments believe that the way to achieve this is to use adaptive strategies. Automated methods that quantify the accuracy of DIR results and the accuracy of the actual patient dose have to be developed before adaptive strategies can be implemented in the clinic on a large scale. With the TEST method the accuracy of DIR results can be quantified and the determination of the expansion, shear strain, and transitivity can be automated. Therefore, the TEST method can be an important tool in the clinical introduction of adaptive radiotherapy. Figure 1: a) shows the deformation vector field projected on the deformed image, where the length of the deformation vectors was magnified three times. In b) the same deformed image is shown in combination with the expansion calculated from the deformation vector field. It can be seen in the orange circle in b) that the vertebrae have an expansion of about 0.15, while the limit is set to 0.01 for bone, therefore this is not an acceptable deformation. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH: For the deformations from pCT to rCT, the target registration error showed minor variation between the different algorithms, as shown in table 1. However, the expansion and shear strain of the DVF (deformation vector field) showed a larger difference. The Demons algorithm exceeded the limits on almost all aspects; for example 5.8% of the soft tissue voxels are out of limit for the expansion. The B-Spline and the SFBR both stayed within the limits for soft tissue and air cavities. The expansion and shear strain in the bony anatomy exceeded the limits for all algorithms. The average transitivity exceeded the limits for SFBR, while it remained within limits for B-Spline and Demons. 20 PHYSICS | 2ND ESTRO FORUM - REPORT Table 1: Overview of the accuracy of deformations with the B-spline, Salient Feature Based Registration (SFBR) and Demons algorithm from the planning CT to a repeat CT for ten different patients. The proposed limits for clinical use are indicated. 2ND ESTRO FORUM - REPORT | PHYSICS 21 4 5 KILOVOLTAGE INTRAFRACTION MOTION MONITORING AND TARGET DOSE RECONSTRUCTION FOR LIVER SBRT DELIVERED BY VMAT AN ALGORITHM TO ASSESS THE NEED FOR CLINICAL MONTE CARLO DOSE CALCULATIONS FOR PROTON THERAPY FIELDS By Per Rugaard Poulsen By Marta Bueno Aarhus University Hospital, Denmark CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Tumors in the thorax or abdomen may undergo substantial breathing motion during radiotherapy beam delivery. The respiratory motion is a challenge for the accuracy in stereotactic body radiotherapy (SBRT), where high radiation doses are delivered in a few treatment fractions to small lesions. The motion may result in target doses that differ markedly from the planned dose. ABSTRACT OVERVIEW: Five patients with implanted gold markers were treated with VMAT liver SBRT in three fractions. Intra-treatment x-ray fluoroscopy with an On-Board Imager was used to estimate the 3D target motion throughout all treatments (Figs 1a-c). The accuracy of the 3D estimations was determined using portal images whenever the tracked gold marker was inside the VMAT field aperture (Fig. 1, bottom). For each treatment fraction, the measured 3D trajectory was used to reconstruct the delivered target dose distribution by a previously validated method that models the target motion as a sequence of isocenter shifts in the treatment planning system (Fig. 1d). WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? The main findings were that: 1. The standard imaging system of a conventional linear accelerator can be used to measure the time-resolved 3D target trajectory during VMAT beam delivery with sub-millimeter accuracy. 2. Even with daily image-guided patient setup, the dosimetric impact of intrafraction target motion can be substantial. The largest observed impact was a reduction of D95 (the minimum dose to 95% of the CTV) from 98% in the plan to 82% in the delivered fraction dose. 3. The presented methods provide useful tools for dose prescription evaluation, e.g. to evaluate whether it is optimal to have the current dose prescription with a peaked, non-uniform PTV dose that gradually decreases from >95% to >67% between CTV and PTV. 22 PHYSICS | 2ND ESTRO FORUM - REPORT Institut de Tècniques Energètiques (Universitat Politècnica de Catalunya), Barcelona, Spain and Institute for Bioengineering of Catalonia, Barcelona, Spain. WHAT IMPACT COULD YOUR RESEARCH HAVE? The demonstrated methods provide a widely accessible approach for intra-treatment motion monitoring and dose reconstruction since only standard equipment of a conventional linear accelerator was used. The reconstructed dose distribution that accounts for the actual intrafraction motion provides a strong tool for (1) quality assurance of individual treatments, (2) optimization of margins and dose prescription approaches in SBRT, and (3) improved understanding of dose-response relationships in radiotherapy outcome studies. With robust automatic real-time segmentation of the gold markers in the kV images the target motion monitoring can be used for real-time adaptation of the beam to the target motion. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Radiation oncology has seen an increasing interest in IGRT for improved patient setup accuracy prior to treatment. The current work brings this development a step further by using IGRT for intra-treatment motion monitoring and individualized reconstruction of the delivered target dose. Another exciting topic is tumor tracking where continuous monitoring is used for real-time beam adaptation during treatment delivery. So far, robotic tracking and gimbal tracking have been implemented clinically using highly specialized treatment machines (Cyberknife and Vero, respectively). The current work demonstrates that the standard IGRT equipment of conventional linear accelerators provides the necessary tools for image-based motion monitoring during beam delivery, which may be used for couch tracking or MLC tracking on conventional treatment machines. CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: In proton therapy, dose distributions inside the patient must be accurately determined to ensure a successful treatment outcome. Patient tissue heterogeneities pose a challenge to current analytical dose calculation algorithms such as the pencil beam (PB) method. Multiple Coulomb scattering causes the degradation of the Bragg peak when a proton beam traverses complex inhomogeneous media. Commonly, PB algorithms model this effect within the dose kernel itself but the radial distribution at each depth only accounts for heterogeneities upstream of the pencil central axis. The assumption of such slab geometry might induce large dose errors in the presence of lateral heterogeneities. The detrimental consequences of such dose calculation deficiencies become more important as the target volume is reduced and the shadow effects due to the presence of heterogeneities have a greater impact on the overall dose coverage in the tumour. An alternative is to use Monte Carlo (MC) calculations, which can provide highly accurate doses and are considered to be the benchmark. However, they are likely to entail long computation times, which is not practical for routine clinical work. ABSTRACT OVERVIEW: We aimed at obtaining an index capable of estimating the level of tissue heterogeneities within the beam path that could be used as an indicator for the accuracy of dose delivery based on analytical dose calculations for small proton fields. We defined a heterogeneity index (HI) that computes, for each field, the lateral tissue heterogeneities following the dose calculation approach taken by the PB algorithm. The PB predictions were verified against MC simulations in terms of dose to the target (GTV) for a number of patients. Finally, we evaluated the correlation between HI and the dose error in the GTV. a good indicator for the accuracy of proton field delivery in terms of GTV prescription dose coverage. Third, with the established correlation a threshold value – HIthres – can be used to identify those patients for which MC recalculation is recommended. WHAT IMPACT COULD YOUR RESEARCH HAVE? The HI can be obtained in less than three minutes, allowing routine clinical implementation of this methodology to readily predict whether a specific field arrangement is associated with significant absolute dose uncertainties. If this were the case, either a change in the beam incidence (if feasible) or a MC dose calculation of the plan should be considered. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Although PB algorithms can provide accurate dose distributions in the absence of complex density heterogeneities, dose predictions might be questioned when the proton beam traverses very inhomogeneous regions in the patient, which is the situation for most head and neck tumours. The HI as defined in this study estimates the reliability of the PB dose predictions in a straightforward manner so that the plan can rapidly be either accepted, if HI<HIthres, or rejected, if HI>HIthres. The efficiency of the HI algorithm leaves the workflow in the clinics unaltered. When HI>HIthres, MC dose calculations can significantly improve the reliability of dose distributions. This may lead to a beneficial increase in tumour control probability for the patient, which is worth the relatively long computation time. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH: The three main findings of our research were the following. First, errors in dose delivered to the GTV predicted by the PB algorithm were up to 5.4%, which exceeds current tolerance levels. For these cases, using MC calculations is warranted. Second, the errors were strongly correlated to our HI (Spearman’s ρ=0.8), which demonstrates that HI is 2ND ESTRO FORUM - REPORT | PHYSICS 23 RTT OVERVIEW OF THE RTT MEETING COMPONENT At the 2nd ESTRO forum in Geneva, the RTT track included presentations on current research and innovation within all aspects of the RTT profession. Of these, we have selected three abstracts that best illustrate the current status of the RTT profession in relation to target and OAR delineation as well as treatment planning. Peter de Ruiter from The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital discussed the efficacy of a VMAT ‘library plan’ solution to deal with bladder volume variations in chemo-radiation therapy of cervical cancer. This research indicated how departments can utilise cone-beam CT and the expertise of their RTTs to optimise their workflow strategies to best meet the need for adaptive processes, in this era of personalised radiation therapy. Introduction OVERVIEW OF THE RTT MEETING COMPONENT p 25 1_ A PLANNING STRATEGY FOR GENERATING A LIBRARY OF PLANS FOR CERVICAL CANCER p 26 2_ DELINEATION OF ORGANS-AT-RISK IN THE PELVIC AREA: DEVELOPING GUIDELINES FOR RTTS p 28 3_ CAN O-MAR INCREASE PRECISION OF DELINEATION IN HEAD AND NECK CANCER? p 30 Bruno Speleers and Maddalena Rossi from University of Ghent, Belgium and the NKI, Amsterdam, respectively, presented their research on the development of guidelines for the delineation of OARs in the pelvic region for RTTs, whose centres are involved in EORTC clinical trials. The first aim of this research was to assess logistical and evaluation methods. The second aim was to investigate interobserver variability when general guidelines for delineation were provided to observers. Based on these results, the final aim of this ongoing research is to determine the interobserver variability when more rigorous guidelines are provided to RTT participants. This presentation at the Forum highlighted the importance of unambiguous guidelines in increasing precision in the delineation process by RTTs. Our final abstract also focuses on the important topic of precision in delineation, this time in the head and neck region. Rasmus Christiansen and his colleagues from Odense University Hospital and the University of Southern Denmark, Institute of Clinical Research presented their research on the ability of the commercially-available ‘Metal Artefact Reduction for Orthopaedic Implants’ (O-MAR) algorithm to increase delineation precision in the head and neck, where metallic dental implants can cause significant streaking artefacts. Dice indices comparing delineations with and without the O-MAR algorithm were reported for the GTV-T, GTV-N and parotid glands, with interesting results. We hope you enjoy this selection of abstracts from the RTT track of the second ESTRO Forum in Geneva, which best represents current RTT research in the fields of delineation and treatment planning. Danilo Pasini Chair of the RTT Meeting 24 RTT | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | RTT 25 1 A PLANNING STRATEGY FOR GENERATING A LIBRARY OF PLANS FOR CERVICAL CANCER By Peter de Ruiter The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: WHAT IMPACT COULD YOUR RESEARCH HAVE? ABSTRACT OVERVIEW: IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Inoperable cervical cancer can be treated with chemo-radiation therapy. The radiation dose is delivered not only to the cervix, but also to the uterus, as (microscopic) tumor invasion may be present there. The uterus lies on top of the bladder, and thus moves on a day-to-day basis due to variations in bladder filling. These movements can be large, up to 5 cm. To deal with these variations, we use a Library of Plans (LoP), consisting of 4 treatment plans for the same patient with various bladder fillings (ranging from full to empty). At each treatment fraction, the most appropriate plan is selected at the Linac, based on a conebeam CT image acquired prior to treatment. The concept of a LoP is an effective solution to cope with the day-to-day variation of the target volume for cervical cancer. It is a challenge though to fit the creation of a LoP into the clinical workflow, as it is time-consuming to make 4 Volumetric Modulated Arc Therapy (VMAT) plans for one patient. The purpose of this study was to develop a planning strategy for generating a clinically acceptable library of 4 “Library Plans” (LP1-4), within an acceptable time period. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? The method we developed makes it possible to generate 4 clinically acceptable plans for different bladder filling situations for cervical cancer, without the need of creating 4 CT scans, delineating targets and OARs on 4 scans and manually constructing 4 separate treatment plans. As the script automatically generates the plan LP1, 3 and 4, the planning time remains acceptable. Using a LoP may improve target coverage without increasing dose to OARs and, as motion is compensated for, margin and thus toxicity on OARs could be reduced. The concept of LoP might also be used for other target areas with a predictable variation in either position or shape, such as bladder tumours. The trend of personalisation and adaptation of treatment plans is expected to improve the quality of each individual treatment, however it also generates a severe pressure on RT departments. Treatment plans are getting more complex and more plans might need to be made for a single patient. RT departments must therefore search for methods that make it possible to handle the increasing amount of work. This research is a good example on how RT departments can work on optimising their workflow for adaptive strategies. Fig 1: Library of plans for cervical cancer. LP1 represents the full bladder situation (100%), LP4 the empty bladder situation (0%). CTVs for LP2 and LP3 are reconstructed based on LP1 and LP2. Initial treatment planning takes place on LP2, as this is expected to be the most common situation during treatment. All other plans are generated automatically. The aqua-blue line represents the 95% isodose line of the prescribed dose. In our method, one initial VMAT plan needs to be manually created for the target volume, corresponding to the 66% bladder filling. Based on this plan, three additional plans are generated automatically for modified target volumes corresponding with bladder filling of 100%, 33%, and 0%, respectively (Fig 1). All plans are made on the same CT scan. The study showed that the automatic plan generation leads to homogeneous plans, with adequate PTV coverage (Table 1). The conformity index (CI V95%) indicated a good sparing of tissue outside the PTV. To validate the safety of planning the non-full bladder situations (LP2-4) on a full bladder scan, the LP4 plans were transferred to the empty bladder scans and dose was recalculated and evaluated. This showed a comparable PTV coverage. Table 1: Results for the total PTV of 5 patients. The plans indicated with a * indicate a plan automatically generated from LP2. The data indicated by LP4** is the plan calculated as LP4*, recalculated on the empty bladder scan. CI V95% is defined as the volume of the 95% dose region divided by the volume of the PTV. 26 RTT | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | RTT 27 2 DELINEATION OF ORGANS-AT-RISK IN THE PELVIC AREA: DEVELOPING GUIDELINES FOR RTTS By Bruno Speleers and Maddalena Rossi University of Ghent, Belgium and NKI Amsterdam, The Netherlands CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: The EORTC performs numerous multi-centre trials, many involving radiotherapy. Target areas for radiotherapy are delineated on CT scans with or without the help of other image modalities by the Radiation Oncologist. However, organs-at-risks (OARs) are delineated in most institutes by a Radiation TechnologisT (RTT). The delineation is frequently based on CT-scans and performed during the treatment planning procedure. Defining strict guidelines on CT based information would reduce the inter-observer variability between institutes. ABSTRACT OVERVIEW: The purpose of the research was to define delineation guidelines for organs at risk (OARs) for RTTs involved in EORTC multi-centre clinical trials. Prior to commencing the study, logistics and evaluation methods were assessed using an OAR (bladder) within a small group of RTTs. In the second phase the same institutes were involved with general guidelines provided for the observers for the OARs in the pelvic region (bladder,anus, rectum, sigmoid, femoral heads and penile bulb). Guidelines were adjusted for those OARs demonstrating large variances between observers. The third phase involves a larger number of observers with stricter guidelines for the same set of OARs. A software package developed in the NKI-AVL, Amsterdam was used for delineation and assessment of delineation accuracy. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Delineation errors still need to be taken into account when calculating the margin expansions between CTV (clinical target volume) and PTV (Planning target volume). Delineation errors and variability should be taken into account. One option, still the object of scientific discussion, could be to calculate these delineation uncertainties in the margin expansions between CTV (Clinical Target Volume) and PTV (Planning Target Volume). Many studies have shown large variations between observers in target volume delineation. These discrepancies also occur in delineations of organs at risk. Research into automatic segmentation algorithms is ongoing for target areas and OARs. However, these automatic segmentation algorithms are not currently in general use. Therefore, in current practice, providing accurate delineation guidelines for OARs could assist in a more optimal objective toxicity scoring and provide a more accurate evaluation of a clinical trial. Fig 1 Fig 2 Example of the discrepancy between observers for the delineation of the rectum (fig 1) and sigmoid (fig 2) especially at the cranially and caudally border of the structure. Scale from blue to red. Blue means a good correlation between observers (small standard deviation) and red, a standard deviation of ≥ 1 cm between observers WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? Large variations were seen between observers especially in the cranial and caudal delineations of the OARs where guidelines were not well defined. Strict guidelines describing anatomical borders are required for OAR delineation in order to avoid discrepancies and reduce variation in OAR delineation. WHAT IMPACT COULD YOUR RESEARCH HAVE? Providing guidelines for delineating OARs in EORTC radiotherapy studies will allow for a more accurate comparison and evaluation of treatment results in multi-centre trials. 28 RTT | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | RTT 29 3 CAN O-MAR INCREASE PRECISION OF DELINEATION IN HEAD AND NECK CANCER? By Rasmus Lübeck Christiansen Odense University Hospital, Denmark CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Delineation of the GTV is a main source of inaccuracy in radiotherapy (RT) planning for Head and Neck Cancer partly because precise delineation is often impaired by artefacts from metallic dental implants affecting visualisation of the tumour and organs at risk (OAR). Imaging modalities less susceptible to metal artefacts, such as PET and MRI, are widely used to compensate for this, but can at the same time introduce new causes of inaccuracies. Therefore, elimination of artefacts on CT scan is still desirable. An image processing algorithm (O-MAR) has been developed to reduce artefacts from orthopaedic metal implants. It has previously been shown that this algorithm has very little effect on the dose calculation (Hansen CR, et al.IJROBP, vol. 84 issue 3, 2012, p. S520-S521). However, its effect on delineation has not been tested so far. ABSTRACT OVERVIEW: This study investigates whether the O-MAR algorithm has an effect on the delineation of GTVs and OARs in Head and Neck Cancer patients. For this purpose, 11 patients planned for curative RT (66-68 Gy/33 Fx) for oropharyngeal carcinoma were included in this study based on streaking artefacts in the tumour area. These 11 patients constituted 20 % of all curative Head and Neck Cancer patients scanned during this period. Three experienced clinical oncologists and one radiologist first contoured the GTVs on standard CT reconstructions without the O-MAR algorithm. Approximately one month later, the GTVs were delineated on the same 11 CT data sets, this time reconstructed with O-MAR. Likewise, 4 experienced RTTs contoured the parotid glands on both reconstructions. The parotid glands were included in this study as they are often affected by metal artefacts. To evaluate inter-observer variation, mean of SørensenDice indices for all combinations of contour pairs, in each reconstruction dataset, was calculated. The results are summarised in Table 1. Reduction of major metal artefacts with O-MAR reconstruction resulted in larger volumes of all delineated structures compared to standard reconstruction. Delineation of the parotid glands also showed a decrease in inter-observer variation after reduction of metal artefacts. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? Reduction of metal artefacts has the potential to improve the delineation of GTVs and OARs, both regarding inter-observer variation as well as volume-wise. Although the decrease in inter-observer variation was not statistically significant for all structures delineated in this study, we were able to demonstrate large and clinically relevant delineation differences in the individual patient before and after artefact reduction, as shown in Figure 1. Volumes of delineated structures are generally larger after reduction of metal artefacts. This may be interpreted as a result of the delineators’ reluctance to delineate in areas void of signal. WHAT IMPACT COULD YOUR RESEARCH HAVE? This study shows that delineation of tumour and OARs in Head and Neck Cancer may be affected by metal artefacts which can ultimately lead to altered RT plans. At Odense University Hospital, O-MAR has become standard for all curative Head and Neck Cancer patients. It is important to keep in mind that metal artefacts may affect the delineation as well as dose calculation. It is plausible, that these results for Head and Neck Cancer patients may be extrapolated to other patient groups. Table 1. Mean Sørensen-Dice indexes and mean volumes of delineated structures +/- Standard Deviation on standard and O-MAR reconstructions. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Quality of OAR delineation in radiotherapy planning is a priority, mainly focused on delineation training of RTTs. Also, supplementary imaging modalities such as MR and PET are introduced for dose planning. However, CT based dose planning is the foundation of dose calculation as well as OAR delineation. Therefore, the image quality of CT scans must still have high priority in our daily routines. Figure 1. Example of GTV-Tumour delineated on the same CT scan, by the same oncologist before and after reduction of metal artefacts with O-MAR. 30 RTT | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | RTT 31 BRACHYTHERAPY Introduction OVERVIEW OF THE GEC-ESTRO-ISIORT MEETING COMPONENT 1_ HIGH DOSE RATE (HDR) BRACHYTHERAPY TREATMENT VERIFICATION USING AN ELECTRONIC PORTAL IMAGING DEVICE (EPID) OVERVIEW OF THE GEC-ESTRO-ISIORT MEETING COMPONENT We had an excellent selection of high-quality proffered papers for the GEC-ESTRO meeting within the ESTRO Forum 2013. These reflect many aspects of modern image guided brachytherapy. Alongside this there are important mature clinical results which underpin our practice. To highlight some of the more important abstracts received, we incorporated, a ‘best of brachytherapy’ proffered paper session into the programme where these were given added prominence. p 33 p 34 2_ HDR BRACHYTHERAPY DOSIMETRIC PREDICTORS OF BIOCHEMICAL CONTROL OF PROSTATE CANCER p 36 3_ DOSE-RESPONSE FOR LOCAL CONTROL IN IMAGE GUIDED CERVIX BRACHYTHERAPY IN THE RETROEMBRACE STUDY p 37 4_ BRACHYTHERAPY IN THE TREATMENT OF ANAL CANAL CANCERS: A LARGE MONOCENTRIC RETROSPECTIVE SERIES. p 38 5_ HDR BRACHYTHERAPY OF THE BASE OF TONGUE. TEN-YEAR RESULTS OF A PROSPECTIVE STUDY p 40 The first of these highlights a new treatment verification system –developed in Melbourne – based on electronic portal imaging for high dose rate brachytherapy. This illustrates the way in which brachytherapy parallels modern external beam radiotherapy, incorporating real time imaging and high levels of quality assurance in treatment delivery. The theme of quality assurance is taken further by the paper from Mount Vernon showing for the first time that implant quality is important in high dose rate brachytherapy for prostate cancer. This has been shown previously in several series of low dose rate brachytherapy and the additional data for HDR, highlights the need for post implant dosimetry and meticulous attention to technique to ensure optimal results. This data is also able to propose a dose response for biochemical control of prostate cancer across the high dose range with a cut-off around the median value of 104Gy (EQD 2). One of the major advances in brachytherapy in the last decade has been the advent of image guided techniques for cervix cancer. This has culminated in the Embrace initiative, which coordinates multi-centre experience in this technique. A retrospective analysis from the Embrace centres – all delivering high quality image guided brachytherapy for cervical cancer – is one of several papers presented at this meeting from that group. Again this shows a dose response for local control in cervical cancer with a threshold D90 for the high risk CTV of between 85 and 93Gy in advanced disease. This data is critical in defining optimal treatment regimes in this setting. Brachytherapy for anal canal cancers is well recognised as an effective treatment, although with the widespread use of chemo radiation and more complex external beam techniques it has not been as widely practiced as in the past. We have therefore given prominence to an important series from Lyon representing one of the largest long term datasets in this disease. They report a 10 year local control rate of 73.9% in 209 patients. Such mature and impressive datasets support the further development of this approach in the radical treatment of anal canal cancer. Head and neck cancer is another site where brachytherapy has proven highly effective in the past, but current practice often favours surgery or complex external beam chemoradiation. Again, therefore, it is reassuring to find the mature data from Budapest on high dose rate brachytherapy to the base of tongue of 60 patients having advanced disease. They report 10 year follow up data, showing a 5 year local control rate of 57%. Once again the outstanding results obtained in this series are strong support for on-going efforts to increase the use of brachytherapy in head and neck cancer. In addition don’t miss out on reading the abstract from Leuven in the Awards section of this report, which has been selected for the Best Junior Presentation Award. This addresses the important area of boost radiotherapy to the breast where brachytherapy has an important and increasing role. This is another mature series, with almost 9 year follow up of 1381 patients evaluating three different boost techniques and demonstrating the efficacy of brachytherapy in comparison to electrons or photon techniques. The above represent just a few of the exciting programme highlights that we had at the ESTRO forum where the entire spectrum of brachytherapy practice was represented. We hope you derived considerable benefit from these and the other presentations included in the programme and that they will inspire and stimulate future brachytherapy research and practice. Peter Hoskin Chair of the GEC-ESTRO-ISIORT Europe Meeting 32 BRACHYTHERAPY | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | BRACHYTHERAPY 33 1 HIGH DOSE RATE (HDR) BRACHYTHERAPY TREATMENT VERIFICATION USING AN ELECTRONIC PORTAL IMAGING DEVICE (EPID) By Ryan L Smith School of Applied Sciences and Health Innovations Research Institute, RMIT University, Melbourne, Australia & William Buckland Radiotherapy Centre, The Alfred Hospital, Melbourne, Australia. CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: High dose rate (HDR) brachytherapy treatment delivery currently lacks a comprehensive verification system. Accurate treatment delivery requires correct source dwell positions and dwell times to be administered relative to each other and to the surrounding anatomy. As high doses are delivered in seconds, and mistakes in an individual fraction cannot be easily rectified, a high standard of quality assurance is required. This work details a system that can potentially satisfy the requirements of verifying both geometric and dosimetric information. ABSTRACT OVERVIEW: We describe a new real-time in vivo verification system for HDR brachytherapy employing an electronic portal imaging device (EPID). Extensive characterisation of the EPID was undertaken to yield appropriate correction factors necessary for this novel application. To demonstrate the utility of the approach for treatment verification, a treatment plan was delivered to a phantom and the planned dose was compared to the dose distribution determined from the EPID measurements. The source position in 3D was also determined accurately from the EPID images. The system thus has the potential to identify incorrect dose delivery to patients in real-time. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? 1. This work describes the first real-time in vivo position- and dose-verification system for HDR brachytherapy. Following comprehensive characterisation, we have demonstrated that an EPID device, originally designed as a patient positioning tool for external beam radiotherapy, can provide source position and two-dimensional dosimetric information when used with an 192Ir HDR brachytherapy source. 2. The position of the source can be determined to be better than ± 0.5 mm in the x,y plane (i.e. the plane of the EPID) up to a source to detector distance (SDD) of 150mm. The resolution of the z coordinate (perpendicular distance from the detector plane) is SDD-dependent with 95 % confidence intervals of ± 0.1 mm, ± 0.5 mm and ± 2.0 mm at SDDs of 50, 100 and 150 mm respectively. 34 BRACHYTHERAPY | 2ND ESTRO FORUM - REPORT 3. The dose can be monitored real-time (dwell-bydwell) during treatment. The total dose distribution can be calculated via integration of individual dwells and likewise the total distribution can be deconvolved into its constituent contributions. Dose differences between planned (TG-43) and measured doses are less than 2 % for 98 % of voxels. WHAT IMPACT COULD YOUR RESEARCH HAVE? The clinical implementation of this system will provide HDR brachytherapy treatment with a mechanism to validate the dose delivery and ‘trap’ errors that are not currently identifiable. It also has the potential to identify implant movement within the patient, thus allowing plan modification before treatment delivery. As well as online verification, the system can capture the dose delivered to the patient as a record of treatment delivery. As a pre-treatment quality assurance verification tool, the system could be used to highlight calculation discrepancies (in a similar way to IMRT, whereby plans are recalculated and delivered to a phantom). IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? With advances in technology in the external beam radiotherapy (EBRT) realm, the drive has been to deliver higher doses in a conformal approach using available imaging technology to ensure patient safety. HDR brachytherapy treatment is inherently a highly conformal modality, but it currently lacks the advanced treatment verification and patient safety mechanisms available in EBRT. Implementing this system routinely in the clinic would push HDR brachytherapy treatment verification forward and in line with EBRT trends. Figure 1. (a) The planned dose distribution after the delivery of 3 out of the planned 6 dwell positions. (b) The integrated EPID image for the delivered dwell positions. (c) The difference between the planned dose and the measured dose in percentage. 2ND ESTRO FORUM - REPORT | BRACHYTHERAPY 35 2 3 HDR BRACHYTHERAPY DOSIMETRIC PREDICTORS OF BIOCHEMICAL CONTROL OF PROSTATE CANCER DOSE-RESPONSE FOR LOCAL CONTROL IN IMAGE GUIDED CERVIX BRACHYTHERAPY IN THE RETROEMBRACE STUDY By Peter Hoskin By Kari Tanderup Mount Vernon Hospital, UK CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: High Dose Rate brachytherapy is widely used for dose escalation with external beam therapy. This study evaluates the importance of implant quality as measured by the dose to 90% of the tumour volume (D90) and volume receiving 100% dose (V100) in relation to biochemical relapse free survival in a prospective cohort. ABSTRACT OVERVIEW OF: We have shown in a prospective randomised trial that dose escalation in prostate cancer using HDR brachytherapy in combination with external beam radiotherapy is effective and results in improved biochemical relapse free survival with no increase in toxicity. To determine whether implant quality as measured by various dosimetric parameters, in particular D90 and V100 are important in predicting outcome in this setting we have evaluated the dosimetry of implants performed in the brachytherapy boost arm of that trial. Since the external beam component was homogenous and constant (35.7Gy in 13 fractions) analysis of total dose delivered including the implant component provides information on both the importance of good implant dosimetry and the dose response for prostate cancer. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? 1. A progresssive, dose related increase in biochemical control of disease is seen with increasing D90 and V100. 2. Based on 5 year biochemical RFS multivariate analysis shows that the most predictive parameters for biochemical control were implant D90 (p<0.004) and V100 (p<0.0004). Presenting PSA and use of ADT were two other factors which had a lesser but significant, predictive effect. 3. A target D90 of 108% is recommended on the basis of this data, representing the median value of the distribution. This is equivalent to a total HDR dose of 17.6Gy (prescription isodose 17Gy) and when converted to an equivalent dose in 2Gy per fraction (EQD2) including the external beam component equates to a target dose of 104Gy EQD2. 36 BRACHYTHERAPY | 2ND ESTRO FORUM - REPORT Aarhus University Hospital, Denmark WHAT IMPACT COULD YOUR RESEARCH HAVE? This data highlights the importance of careful dosimetry when undertaking HDR prostate brachytherapy and parallels the experience with low dose rate (LDR) seed brachytherapy for prostate cancer. The flexibility of HDR delivery with variable dwell times defined before exposure gives greater opportunity to improve the dose delivered and the target D90 of 108% should be attained wherever possible. It also highlights the importance when using a single step procedure under anaesthetic of correcting a poor implant before proceeding to treat the patient. The derivation of a threshold target dose of 104Gy is in keeping with other data from the HDR literature evaluating dose escalating schedules and suggests that for localised prostate cancer a dose response up to and beyond 100Gy exists. This then provides a rationale for all techniques, whether brachytherapy, image guided external beam therapy or stereotactic radiotherapy to aim for doses in this range ensuring that tumour dose is not attained at the expense of normal tissue constraints. This aim of achieving maximum tumour control with acceptable toxicity is readily achieved with HDR brachytherapy. CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Locally advanced cervical cancer is treated by external beam radiochemotherapy followed by brachytherapy. During the last decade, significant progress has been demonstrated with integration of MRI in the brachytherapy planning procedure. MRI is used to assess the tumour response after external beam radiotherapy and to individualise the brachytherapy dose to the individual patient according to size and response of the tumour. Pioneering institutions started MRI guidance more than 15 years ago and the GEC ESTRO gyn working group was established in year 2000. Building on these efforts a core group of European and international centers (GEC ESTRO gyn network) was established in year 2005 with the aim of further development and promotion of MRI guided brachytherapy in research and through a multicentre clinical study, EMBRACE (International study of MRI guided brachytherapy in cervix cancer). RetroEMBRACE is a retrospective study that has collected data from 12 institutions, from Europe and Asia, who performed MRI guided brachytherapy previous to 2008 when the EMBRACE study was initiated. ABSTRACT OVERVIEW: Currently, there is no solid evidence for the optimal dose prescription in brachytherapy for cervical cancer, and there is a wide variation of dose levels and brachytherapy fractionation schedules applied. The retroEMBRACE dose response study comprises data from 592 patients from 12 institutions. Dose prescription varied significantly between institutions and within each institution with a variation in prescribed dose of 14Gy (SD) with a mean of 87Gy. This significant heterogeneity in dose prescription allowed for an extensive analysis of dose response. The purpose of this research project was to evaluate dose response relationship for local control in locally advanced cervical cancer for the entire patient population and for subgroups according to different risk criteria. 3. The finding of a dose response relationship demonstrates that the adaptive target concept (HR CTV), which has been developed for MRI guided brachytherapy, is highly relevant for local control and is robust in a multicenter setting of centers experienced in MRI guided brachytherapy WHAT IMPACT COULD YOUR RESEARCH HAVE? With the new retroEMBRACE evidence for dose response, it will be possible for institutions to change their dose prescription in order to optimise the balance between local control and morbidity. The next logical step for future clinical studies within locally advanced cervical cancer is to install dose constraints which may lead to improved local control. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? There is currently a huge interest in adaptive radiotherapy. MRI guided brachytherapy in cervix cancer is a very interesting adaptive model which directly takes into account the response during radiotherapy. The upcoming ICRU report on brachytherapy in cervix cancer introduces systematically an adaptive CTV concept based on repeated imaging and clinical examination during radiotherapy. This adaptive CTV concept has much potential in other cancer sites, in particular those characterised by significant tumour regression during radiotherapy, such as head and neck, rectum and lung. Furthermore, the application of highly focal boost doses to a high risk CTV combined with administration of intermediate doses to an intermediate risk CTV has demonstrated excellent local control in cervix cancer. Such a risk adapted model with application of heterogeneous dose distributions is also of great interest for other cancer sites. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? The three main findings of the retroEMBRACE dose response study are: 1. retroEMBRACE establishes evidence for a clear dose response relationship in locally advanced cervical cancer 2. retroEMBRACE demonstrates that a high local control rate can be obtained with the use of MRI guided brachytherapy: local control of >90% is possible with doses >90Gy to the high risk CTV. Figure 1. Dose response relationship for local control. 2ND ESTRO FORUM - REPORT | BRACHYTHERAPY 37 4 BRACHYTHERAPY IN THE TREATMENT OF ANAL CANAL CANCERS: A LARGE MONOCENTRIC RETROSPECTIVE SERIES. By Laëtitia Lestrade Centre Léon Bérard - Radiation Oncology Department, Lyon, France CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Anal canal cancers are rare. External Beam Radiotherapy (EBRT), with concomitant chemotherapy (CT) for advanced tumours, is the standard treatment for anal canal carcinoma. Some retrospective studies have shown better local control rates in patients receiving a total dose >5559Gy to the tumour bed. International guidelines support the utility of a boost after the EBRT +/- CT. Brachytherapy (BRT) is considered a valuable technique to deliver the boost to T1-2 and selected small T3 anal tumours responding to EBRT+/-CT, but its role has still not been well evaluated. Indeed, the number of patients treated by BRT in the context of RCTs or in the retrospective series is limited, with only 3 retrospective studies presenting results from a little more than 200 patients. ABSTRACT OVERVIEW: We report data on 209 anal canal cancer (median age: 65 years; range: 26 – 89) patients treated in the period 05/1992 -12/2009 with EBRT (58/209) or EBRT+CT (151/209). All patients underwent a boost delivered with a Low Dose Rate (LDR, 151 patients) or a Pulse Dose Rate (PDR, 58 patients) BRT. After a median follow-up time of 73 months, median LC time was not reached, and 5- and 10- years LC rates were 78.6% and 73.9%, respectively. G3-G4 acute and late toxicity rates were 11.2% and 6.2%, respectively. Grade 3 CT related acute toxicities were recorded in 7/151 patients (4.6%). After the longest follow-up available in the literature of the 4th larger population of anal cancer patients, our data confirm the efficacy and the safety of BRT. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? 1. Benchmark data are strongly needed to evaluate different treatment techniques and modalities, particularly for rare cancers like anal canal cancer. The large size of our series and our long follow-up make this series one of the most important benchmark datasets in this clinical and therapeutic setting. 2. This study is also an important benchmark showing the safety of BRT with rates of 11.2% and 6.2% of acute and late severe toxicity, respectively. 3. In our analysis, a statistical relationship exists between the total BRT dose (<18Gy vs >18Gy) and 38 BRACHYTHERAPY | 2ND ESTRO FORUM - REPORT clinical response by digital rectal examination before BRT, with higher doses delivered to patients showing worse response (p = 0.001), but also with lower doses showing better outcomes (p = 0.003). Moreover, it should be noted that the risk of late toxicity was influenced by the total dose of EBRT and the number of implants, typically both larger in poorly-responding patients. These results could be interpreted as a potential limit of BRT i.e., that BRT cannot compensate for a poor response to EBRT+/-CT, even using higher doses, and moreover could be more toxic in poorly-responding patients. adopting new technologies to optimise economic resources and, therefore, a clear knowledge of the benefits that new and old technologies can provide to patients is strongly expected. BRT has been historically adopted in the treatment of anal canal cancer patients, and our study is one of the most important benchmark datasets on its role in this clinical and therapeutic setting. BRT in the treatment of anal canal cancer should be evaluated and critically compared to the new techniques of irradiation. WHAT IMPACT COULD YOUR RESEARCH HAVE? We confirm with long follow-up in a large population, the role of BRT in the treatment of anal canal patients. We also identify a potential limit of this technique that should be further studied. Finally, this study could be an important starting point for several prospective studies: A prospective randomised study using Health Technology Assessment parameters, comparing BRT and External Beam Radiotherapy to deliver the boost on the tumour bed. Application of Artificial Intelligence and Machine Learning to this large database in order to assess relationships between the different variables. These techniques would potentially offer a new, more advanced way to identify patients that could take advantage of BRT. Feasibility study (phase I/II) to evaluate the potential role of High Dose Rate BRT in this clinical context. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? The role of RT +/- CT in the treatment of anal canal cancer patients has been definitively assessed, but some important concerns still remain about dose and volume of irradiation. Moreover, in the last decade, more advanced technologies have been extensively introduced in the daily clinical practice, such as image-guided radiation therapy, intensity modulated radiation therapy, several advanced dose modulation and delivery techniques. Because of the current economic situation, special attention is required when 2ND ESTRO FORUM - REPORT | BRACHYTHERAPY 39 5 HDR BRACHYTHERAPY OF THE BASE OF TONGUE. TEN-YEAR RESULTS OF A PROSPECTIVE STUDY By Zoltán Takácsi-Nagy Center of Radiotherapy, National Institute of Oncology, Budapest, Hungary CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: In the treatment of base of tongue cancer, definitive radiotherapy is largely used alone or combined with chemotherapy as an organ-preserving method instead of surgery, which often results in poor quality of life due to impairment of speech and swallowing. Interstitial low-dose-rate (LDR) brachytherapy (BT) has been applied for a long time as a boost in the treatment of base of tongue tumors, but only few detailed analyses can be found in the literature about the application and efficacy of high-dose-rate (HDR) BT. ABSTRACT OVERVIEW: We initiated a phase II, prospective investigation to study the feasibility and efficacy of external beam irradiation (EBI) + HDR BT. Between January 1992 and June 2011 sixty patients (mean age 57 years) with T1-4 and N0-3 carcinoma of the base of tongue were treated with HDR BT boost (mean dose 17 Gy) after a mean dose of 62 Gy locoregional EBI. The most frequent fractionation schedule was 5x3 Gy and 5x4 Gy. In 10 cases rigid needles were used, in 50 cases flexible tube technique was applied. Eight patients underwent planned neck dissection. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? survival was between 22 and 44%. With an LDR boost local control at 5 years improved to 64-89%. Five-year overall survival was between 35 and 72%. Severe grade 4 side-effects, soft-tissue necrosis occurred in 2,5-27% and osteoradionecrosis in 0-6%. The five-year rate of local tumor control in our T1-T4 patients treated with HDR boost was 100%(T1), 75%(T2), 61%(T3) and 52%(T4), respectively, while in the boost LDR studies it was on average 85-93%(T1), 50-93%(T2) and 46-82% (T3-T4), respectively. Our results are similar to LDR results. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? The advantage of LDR is that continuous-low-dose irradiation allows redistribution of tumor cells into radiosensitive portions of the cell cycle, prevents tumor repopulation and exploits differential repair capacity between tumor cells and normal tissues. This radiobiological “disadvantage” of HDR BT can be eliminated usingtwice daily fractionation. EBI combined with interstitial HDR BT boost can result in acceptable local control and overall survival. The low incidence of serious late side-effects in our series justifies the use of HDR interstitial BT as a boost treatment. Combination with radiochemotherapy may improve results, but further studies are needed to define the optimal dose and fractionation of HDR BT in the treatment of base of tongue cancer. Implanted catheters into the base of tongue cancer Dose distribution with the cross section of the catheters on CT slice The mean follow-up time for surviving patients was 121 (range 20-229) months. Tumor response to treatment was assessed 2-3 months after completion of the definitive radiotherapy. The complete and partial local remission rate was 77% (46/60) and 23% (14/60), respectively. The 5-year actuarial rate of local-, locoregional control and overall survival was 57%, 50% and 47%, respectively. Overall survival was significantly better in patients receiving radiochemotherapy (n=17) (69 vs. 39%; p=0.005). Delayed soft tissue ulceration and osteoradionecrosis occurred in 8 (13%) patients. No permanent functional damage limiting understandability of speech or normalcy of diet developed. WHAT IMPACT COULD YOUR RESEARCH HAVE? In the past base of tongue cancer has been treated exclusively with external beam irradiation with a five-year local control rate was ranging from 28 to70 %. Five-year overall 40 BRACHYTHERAPY | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | BRACHYTHERAPY 41 RADIOBIOLOGY OVERVIEW OF THE PREVENT MEETING COMPONENT Radiotherapy is, after surgery, the second most important contributor to finding a cancer cure. In the era of targeted therapies, radiotherapy is certainly one of the best exemples of real and precise targeted treament, thanks to the recent progress of physics and balistics. Today over fifty percent of cancer patients in Europe are treated with radiation therapy. However, radiation therapy can still cause disabling normal tissue injury in a subset long-term cancer survivors. Introduction OVERVIEW OF THE PREVENT MEETING COMPONENT p 43 1_ SECOND CANCER RISKS AFTER RADIOTHERAPY FOR BREAST CANCER: WHAT IS THE IMPACT OF ADVANCED TREATMENT TECHNIQUES? p 44 2_ LET DEPENDENT RESPONSE OF THE RAT CERVICAL SPINAL CORD AFTER CARBON ION IRRADIATION p 45 3_ ACE-INHIBITION REDUCES ACUTE CARDIAC DAMAGE TO AMELIORATE RADIATION-INDUCED LUNG DYSFUNCTION p 46 Increasing normal tissue tolerance is therefore a worthwhile goal and a great challenge for modern radiation therapy as exemplified in this third edition of PREVENT. In the next few years the development of individualized treatment will enhance the safety and efficacy of radiation therapy and strong trans-disciplinary interactions between clinicians, biologists, imaging specialists and physists is required to speed up the process. The three selected abstracts use different and complementary approaches, which highlight the recent evolution of our discipline. The recent technical advances both in imaging and high precision dose delivery lead to the evolution of treatment planning toward hypofractionation schedules and safe reduction of targeted volume. While reduction in the irradiated volume is thought to protect normal tissue, radiobiological investigation are required to understand the mechanisms involved and to enhance safety. The study by E Donovan et al. is an example of interdisciplinary translational research where dose distribution, including imaging, was measured in breast cancer patients. It brings important new information, as no unacceptable increased risk of second cancers was predicted after the use of such advanced techniques. The study by Saager et al. uses a well characterized model of late tissue damage of the CNS in rats to assess the accuracy and validity of mathematical modeling and show different effects between high vs low LET irradiations. The last selected study, by Van der Veen et al., shows how precise balistics can affect the outcome in terms of physiopathological injury and shows the importance of irradiated volume, as well as demonstrating some specific interactions between organs included in the irradiation field (here heart and lung). It stresses the importance of accurate targeting in experimental models and shows that personnalized therapeutic modulation can then be successfully applied. Marie-Catherine Vozenin and Jan Alsner Chairs of the PREVENT Meeting 42 RADIOBIOLOGY | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | RADIOBIOLOGY 43 1 2 SECOND CANCER RISKS AFTER RADIOTHERAPY FOR BREAST CANCER: WHAT IS THE IMPACT OF ADVANCED TREATMENT TECHNIQUES? LET DEPENDENT RESPONSE OF THE RAT CERVICAL SPINAL CORD AFTER CARBON ION IRRADIATION By Ellen Donovan* By M. Saager The Royal Marsden and the Institute of Cancer Research CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Breast cancer is the most commonly diagnosed female cancer and, with good survival rates, it is imperative that any potential long term side effects from this effective treatment are reduced. Radiotherapy deliveries specific to patient cohorts with different risk factors for local recurrence are likely to be the new standard of care in breast radiotherapy in 5 to 10 years. The radiotherapy beam arrangements required will distribute the dose throughout the body in a different pattern to the standard treatment, as will the associated imaging at the time of treatment. The aim of this work was to measure dose distributions from these modern radiotherapy techniques (including the imaging) and to use these data to predict the risk of second cancer in a range of organs. ABSTRACT OVERVIEW: Five classes of radiotherapy plans used to treat the whole breast, a partial breast and the whole breast plus the tumour bed were created on a CT dataset. The plans were transferred to a whole body phantom. Regions in the phantom which represented radiosensitive organs were delineated and thermoluminescent dosimeters (TLD) used to measure the dose from the radiotherapy and its associated time-of-treatment imaging. These dose data were used as input into the Biological Effects of Ionising Radiation Report VII models of second cancer induction and lifetime risks calculated for the five treatment classes and intensive imaging regimes. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? The modern complex radiotherapy techniques investigated were not predicted to increase the theoretical risk of second cancer incidence in organs far from the treated breast. Whilst increases in the lifetime risk of induced second cancer in the lungs were predicted for some techniques, these remained small compared to the large reduction in local recurrence risk from receiving radiotherapy as a component of curative treatment. The use of image guidance is unlikely to result in an unacceptable increase in second cancer risk. 44 RADIOBIOLOGY | 2ND ESTRO FORUM - REPORT German Cancer Research Center (DKFZ), Heidelberg, Germany WHAT IMPACT COULD YOUR RESEARCH HAVE? CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: * Ellen Donovan is funded by a National Institute for Health Research CSO HealthCare Scientist award. This report presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. ABSTRACT OVERVIEW: The work contributes to the understanding of the longterm implications of modern radiotherapy treatments on normal tissues. Is this research indicative of a bigger trend in oncology? As the number of cancer survivors increases the long term consequences of treatment, and their impact, will become of greater importance. Particle therapy is an advanced radiation strategy for selected cancer patients. Beside a highly conformal dose delivery, particles such as carbon ions have an increased relative biological effectiveness (RBE), which depends on the dose per fraction, the biological system, the selected endpoint and the linear energy transfer (LET). LET is defined as the energy deposition per unit length and increases along the beam path showing a profound increase of RBE. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Physical and biological advantages are the main reasons why particle therapy has developed into a challenging treatment option during the last decade. In spite of promising results, a concerted action of physical, biological and clinical research is necessary to fully exploit the potential capabilities of particle therapy in radio-oncology. Tolerance doses of the rat cervical spinal cord after photon and carbon ion irradiation were determined and used to calculate RBEs. We conducted a systematic study on the variation in RBE along the carbon ion depth-dose profile using an established in vivo model for radiation induced late normal tissue damage of the CNS. The obtained data allowed us to study and assess accuracy and limitations of a bio-mathematical model, which is used for treatment planning to calculate the RBE. Additionally a MRI and histology-based longitudinal study is ongoing to elucidate the mechanisms of radiation induced myelopathy. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? Compared to historical tolerance data measured in the entrance region of the beam, the irradiation method is stable and reproducible. On the basis of the preliminary analysis the LET effect is clearly visible, meaning that high LET irradiations are more effective than low LET irradiations. WHAT IMPACT COULD YOUR RESEARCH HAVE? To include the RBE in particle treatment planning, bio-mathematical models are required which rely on biologically determined datasets. Systematic in vivo studies on the relationship between the RBE and LET of carbon ions at various positions along the depth-dose profiles may not only be helpful to benchmark the RBE-models but may also be used for the assessment of safety margins. 2ND ESTRO FORUM - REPORT | RADIOBIOLOGY 45 3 ACE-INHIBITION REDUCES ACUTE CARDIAC DAMAGE TO AMELIORATE RADIATION-INDUCED LUNG DYSFUNCTION S.J. van der Veen University Medical Center, University of Groningen, The Netherlands CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Thoracic tumors such as breast, esophagus, lung cancer and Hodgkin’s lymphoma are among the most common human malignancies. The treatment of choice is often radiation therapy. Unfortunately, the radiation dose that can be administered safely is limited by the risk of radiation-induced lung toxicity (RILT), a potentially life-threatening side effect of radiotherapy of thoracic tumors. As such, mitigation of RILT would give opportunities to increase tumor dose and improve local tumor control. Treatment with ACE-inhibitors, commonly used drugs to treat patients with cardiovascular diseases, has shown to ameliorate RILT in rats although the exact mechanism is not elucidated1. Recently, we found that in addition to inflammation, pulmonary vascular remodeling plays an important role in the development of RILT in rats, resulting in pulmonary hypertension, right ventricle hypertrophy and eventually to cardiopulmonary dysfunction2. ACE inhibitors might attenuate these effects. ABSTRACT OVERVIEW: We hypothesized that the protective effect of ACE-inhibition on radiation-induced cardiopulmonary dysfunction might be due to reduced vascular remodeling and pulmonary hypertension. Therefore, in this study we investigated whether ACE-inhibition ameliorates early radiation-induced cardiopulmonary dysfunction by protection of pulmonary vascular remodeling. We excluded or included the heart in the irradiated field to elucidate the exact protective mechanism of ACE-inhibition on early radiation-induced cardiopulmonary function loss. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? At 8 weeks post-irradiation, the peak of early radiation-induced pulmonary/cardiac dysfunction, breathing rate measurements showed that captopril administration significantly improved the rats’ cardiac/pulmonary function, but only when the hearts were included in the radiation field. This protective effect could not be explained by protection of the pulmonary vasculature or pulmonary artery pressure changes, which were equally damaged with or without captopril. Interestingly, besides decreased pleural and pericardial effusion, captopril treated rats had better cardiac function, as shown by left ventricle hemodynamic 46 RADIOBIOLOGY | 2ND ESTRO FORUM - REPORT measurements. In addition, captopril treatment reduced perivascular and interstitial fibrosis in the irradiated hearts indicating that captopril exerts a protective effect by reducing direct acute heart damage and its effect on loss of cardiopulmonary function. WHAT IMPACT COULD YOUR RESEARCH HAVE? The early effects of heart irradiation are recently getting more attention in breast cancer and Hodgkin’s lymphoma patients, since it is believed that they may predict late cardiac damage. Our preclinical studies showed that concomitant irradiation of the heart with the lungs enhanced the risk of early radiation-induced pulmonary dysfunction3. So, irradiation of the heart induces acute cardiac changes, which may play an important role in the development of the lung toxicity after thoracic irradiation. This research shows that the clinically/FDA approved ACE-inhibitors may be a promising strategy to reduce early cardio-pulmonary complications induced by radiotherapy to the thoracic area in patients receiving a dose to the heart. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Radiation treatment plays an important role in the treatment of thoracic tumors. The efficacy of the treatment however, is limited by the sensitivity of unavoidably co-irradiated healthy tissues. Therefore, new strategies are needed to decrease the sensitivity of the co-irradiated healthy tissues and thereby improve the effectiveness of thoracic radiotherapy. In the current study, ACE-inhibition was found to decrease acute radiation-induced cardiac damage. The early effects of heart irradiation are recently getting more attention in breast cancer and Hodgkin’s lymphoma patients, since it is believed that they may predict late cardiac damage. Our preclinical studies show that concomitant irradiation of the heart with the lungs enhances the risk of early radiation-induced lung toxicity (RILT)4. Therefore, clinically/ FDA approved ACE-inhibitors might be useful to diminish early radiation-induced cardiopulmonary toxicity in patients receiving a dose to the heart. Ghosh et al. Int J Radiat Oncol Biol Phys 2009 Ghobadi et al. Thorax 2011 3 Van Luijk et al. Cancer Res 2005 4 Van Luijk et al. Cancer Res 2005 1 2 2ND ESTRO FORUM - REPORT | RADIOBIOLOGY 47 AWARDS AWARDS Dear colleagues, At ESTRO we continue to find it important to recognise those whose work has an especial impact on the field of radiation oncology, its advancement and thereby, inevitably, the care of our patients. We bestow several types of Awards, ranging from Lifetime Achievement Awards, Award Lectures, University Awards, and Company Awards. Several of these Awards, in particular the Award Lectures, are a direct commemoration of our founding fathers and ESTRO’s history; receiving them is considered a great honour. Introduction AWARDS p 49 1_ ESTRO - VARIAN AWARD MOTION SIMULATIONS WITH A STATISTICAL DEFORMATION MODEL TO EVALUATE PTV MARGINS IN LOCALLY ADVANCED PROSTATE CANCER During the 2nd ESTRO Forum we once again distinguished several colleagues for their noteworthy endeavours. The Award Lecture and Lifetime achievement Awards have been highlighted for you on these pages. The following Awards section report provides an overview of the work conducted by the recipients of the ESTRO-Jack Fowler University of Wisconsin Award and the Company Awards. I would like to once again congratulate all these praiseworthy individuals and thank them on behalf of the ESTRO community for their meaningful work. I would also like to extend a word of thanks to the Nominating Committee Members and the Board for their work and the difficult decisions they had to make in regards to making a selection amongst so many outstanding peers. p 50 Vincenzo Valentini President of ESTRO 2_ ESTRO - ACCURAY AWARD RADIOBIOLOGICAL IMPLICATIONS OF RESPIRATORY MOTION IN THE TREATMENT OF LUNG CANCER p 52 3_ ESTRO - NUCLETRON BRACHYTHERAPY AWARD CORRELATION OF DOSE WITH VAGINAL MORBIDITY AFTER MRI-GUIDED BRACHYTHERAPY FOR LOCALLY ADVANCED CERVICAL CANCER The Klaus Breur Award Lecture is the highest honour that can be conferred upon an ESTRO member and is awarded in recognition of a major contribution to European radiotherapy. This annual Award is named after Professor Breur – one of our most eminent founders – and is a tribute to his pioneering work. This year the Award went to Vincent Grégoire from Belgium; he treated us to his lecture on ‘This is not an apple ...’ p 54 4_ ESTRO - JACK FOWLER UNIVERSITY OF WISCONSIN AWARD 2013 BEYOND VMAT - HIGH SPEED DELIVERY OF ROTATIONAL IMRT WITH CONE-BEAM TOMOTHERAPY The Emmanuel Van der Schueren Award Lecture is given in honour of a remarkable figure in ESTRO’s history; E. Van der Schueren is considered by many as being the personification of ESTRO in its early years and his influence on European multidisciplinary oncology made him unique. This year the Award went to Ben Mijnheer from The Netherlands who presented us with his lecture on ‘The role of medical physicists in implementing advanced technology in radiotherapy’. p 56 5_ GEC-ESTRO BEST JUNIOR PRESENTATION SPONSORED BY NUCLETRON MOTION SIMULATIONS WITH A STATISTICAL DEFORMATION MODEL TO EVALUATE PTV MARGINS IN LOCALLY ADVANCED PROSTATE CANCER The Irridium Award lecture is presented to a radiation oncologist or physicist who has made a major contribution to the development of brachytherapy. This year we awarded Joseph Hammer from Austria who presented ‘From low dose rate to high dose rate – a story of success’. p 58 The Honorary Physicist Award Lecture is bestowed upon a non-physicist who has made an outstanding contribution to the cause of physics in ESTRO and has thereby raised the profile of physics in the fields of radiation oncology and clinical radiotherapy. This year Mary Coffey from Ireland received the Award; she presented her lecture entitled ‘Collaboration supports success’. The Lifetime Achievement Awards are handed out by the ESTRO Board to honour Society members who have dedicated their professional life to Radiation Oncology and the work of ESTRO. This year they were conferred upon four deserving individuals: Adrian Begg (The Netherlands), Albert J. van der Kogel (The Netherlands), Michael Bamberg (Germany) and Mary Gospodarowicz (Canada.) 48 AWARDS | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | AWARDS 49 1 ESTRO - VARIAN AWARD This prize is awarded to a radiotherapy professional for research in the field of radiobiology, radiation physics, clinical radiotherapy or radiation technology. MOTION SIMULATIONS WITH A STATISTICAL DEFORMATION MODEL TO EVALUATE PTV MARGINS IN LOCALLY ADVANCED PROSTATE CANCER By Sara Thörnqvist Department of Medical Physics, Aarhus University Hospital, Aarhus, Denmark CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: residual target motion on dose escalations to both the prostate and/or the elective targets. In this setting, the accumulated target dose accounting for the most probable motion patterns can be assessed as a function of heterogeneity of the dose prescription (i.e. dose painting). In addition, the method can be applied to different treatment sites involving irradiation of multiple targets or to further analyse the motion patterns of targets and organs at risk following the work of Söhn et al. ABSTRACT OVERVIEW: IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Radiotherapy of several major tumour sites involves simultaneous treatment of multiple targets, typically occurring when irradiation of both the primary and elective targets is indicated. This study has evaluated the influence of target movements on the required margins with a method allowing for both residual rigid motion as well as shape changes of the targets. In the treatment of locally advanced prostate cancer, the dominating residual geometrical uncertainties following image-guidance can be ascribed to deformations and uncorrelated motion of the involved targets: the prostate (CTV-p), the seminal vesicles (CTV-sv) and the pelvic lymph nodes (CTV-ln). This is a challenge for simultaneous treatment delivery. In addition, the commonly applied margin recipes do not explicitly accommodate deformations and partly correlated movement. The aim of this study was therefore to use a statistical deformation motion model to simulate target motion occurring throughout a course of treatment, for the purpose of margin evaluations. The current project fits the general trend of adaptively individualised radiotherapy. With the increased amount of volumetric imaging information available during radiotherapy, the method has potential to prospectively model and adjust to patient specific motion patterns. The information gained in the initial few fractions of the treatment could thereby allow for modelling of the accumulated dose given with the current treatment plan and adaptations of the plan could further be made for improved target coverage or for dose reduction to organs at risk. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? The statistical motion model (Figure 1) revealed large differences in the patterns of residual motion for the 19 patients included in the study. To account for the observed motion patterns, margins around the elective targets ranged from 3-15mm after image-guidance based on the prostate. Applying similar criteria as for the conventional margin recipes, 5mm margins were required around both the CTV-p and CTV-ln whereas larger margins, 11mm were needed for CTV-sv (Figure 2). WHAT IMPACT COULD YOUR RESEARCH HAVE? The model applied for margin evaluation in the current study could form the basis for investigating the effect of 50 AWARDS | 2ND ESTRO FORUM - REPORT 2ND ESTRO FORUM - REPORT | AWARDS 51 2 ESTRO - ACCURAY AWARD The ESTRO – Accuray Award is handed out to a radiotherapy professional for research in the field of “High Precision Radiotherapy”. RADIOBIOLOGICAL IMPLICATIONS OF RESPIRATORY MOTION IN THE TREATMENT OF LUNG CANCER By Dr Aidan J Cole Queen’s University Belfast, Northern Ireland CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Respiratory motion can affect many aspects of the staging, planning and delivery of radiotherapy treatment in lung cancer. Technological innovations in imaging (e.g PET scanning/4-dimensional CT) enable clinicians to accurately determine the position of lung tumours in all parts of the breathing cycle. Advances in radiotherapy delivery techniques to improve dose delivery and account for respiratory motion have been introduced without full concomitant understanding of the underlying radiobiological response. To date in vitro studies examining such responses have been carried out exclusively under static conditions. The context of this study is to determine whether tumour motion can impact on cancer cell survival when exposed to clinically relevant radiotherapy treatments. ABSTRACT OVERVIEW: In this study we constructed a bespoke motor-driven platform to replicate respiratory motion and study the consequences of tumour cell survival in vitro. (Figure 1) We used a PMMA phantom which could accommodate flasks containing non-small cell lung cancer cells. Using a 6MV linear accelerator we delivered uniform and modulated beams to the cells at varying doses and respiratory rates to determine if tumour motion impacted on cell survival for different conditions. Statistical comparisons were made between in and out of field regions for a number of different experimental set-ups to investigate oscillatory type dose delivery to tumour cells. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? 1. This is the first study in which respiratory motion is applied to a novel in vitro set up to investigate lung cancer cell survival. 2. The presence of respiratory motion in uniform irradiation did not differ from static conditions for cell survival. 3. When shielding was applied there was significantly higher cell survival in-field and out-of-field with res- 52 AWARDS | 2ND ESTRO FORUM - REPORT piratory motion compared to a static set-up. To replicate the dose received by the tumour cells a moving shield and manipulation of the multi-leaf collimators (MLC’s) on the linear accelerator were also used and confirmed these differences when compared with static conditions. (Figure 2) WHAT IMPACT COULD YOUR RESEARCH HAVE? This work defines the need for further studies examining the difference between motion management techniques such as breath hold techniques, respiratory gating and respiratory tracking. Selection of margins for treatment planning volumes may also be influenced by the cell survival patterns measured in this study indicating if margins are too small efficacy may be affected. In addition, modulated radiotherapy techniques such as IMRT/VMAT deliver radiation with a complex relationship between time and spatial dose which may significantly interact with respiratory motion in impacting on tumour cell survival. An improved understanding of the radiobiological responses of these treatments may help with treatment choice and optimising dose delivery. Figure 1 Moving platform set-up. a) Solid water b) Perspex phantom with flask/cells c) Motor unit d) Rotational disc e) Treatment couch f) Linear accelerator g) Platform base h) (inset) lead shielding attached to platform IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? Motion management techniques in radiotherapy are becoming increasingly used, particularly in the era of stereotactic radiotherapy where accounting for tumour motion is integral to safe delivery of high doses of radiotherapy with concomitant sparing of normal tissue. Understanding the interplay between irradiated and un-irradiated cancer and normal tissue cells in the presence of motion may enable us to harness delivery techniques to maximise the tumour control probability and enhance the therapeutic ratio. In vitro studies such as this can guide further investigation into in vivo work to better evidence the introduction of technological improvements in radiotherapy delivery. Understanding the biology behind changes due to new techniques can aid in the development of strategies to target optimised dose delivery. Figure 2 Region of interest for flask (top) and H460 clonogenic survival comparing uniform, static (Stat), motion at respiratory rates (14,21) lateral (lat) motion, and lead shielding with motion (L 14, L21) for in- and out-of-field regions. –IC (= no intercellular communication). 2ND ESTRO FORUM - REPORT | AWARDS 53 3 ESTRO - NUCLETRON BRACHYTHERAPY AWARD This award is granted to the most innovative submitted paper. All abstracts that were submitted and accepted for oral presentation at the GEC-ESTRO-ISIORT Europe meeting, within the 2nd ESTRO forum, were automatically considered eligible for this award. The winning abstract was selected by the GEC-ESTRO-ISIORT Europe meeting experts. CORRELATION OF DOSE WITH VAGINAL MORBIDITY AFTER MRI-GUIDED BRACHYTHERAPY FOR LOCALLY ADVANCED CERVICAL CANCER By Kathrin Kirchheiner1, Remi A. Nout2, Kari Tanderup3 Department of Radiotherapy, Medical University Vienna; 2 Department of Clinical Oncology, Leiden University Medical Center; 3 Department of Oncology, University Hospital Aarhus 1 CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Brachytherapy is an essential part of definitive radio-(chemo)therapy for locally advanced cervical cancer. Recent advances such as the introduction of repetitive volumetric imaging (CT, MRI) and concepts for definition and delineation of target volumes and organs at risk, have led to the concept of image guided adaptive brachytherapy (IGABT). Several institutional series show that IGABT leads to improved local control with simultaneous decrease of treatment related side effects. Patient reported quality of life studies point out that vaginal morbidity and associated sexual dysfunction and symptoms are an important cause of long-term distress in cervical cancer survivors. The ongoing prospective observational EMBRACE study (European and International study on MRI-guided brachytherapy in locally advanced cervical cancer, www. embracestudy.dk) implements IGABT in a multicenter setting to establish a bench-mark for clinical outcome regarding local control, survival, morbidity and quality of life. Vaginal morbidity is prospectively assessed with the Common Terminology Criteria for Adverse Events (CTCAE v.3) in conjunction with dose volume parameters. Follow-up is assessed three months after the end of the treatment for the first year, every six months in the second and third year and yearly thereafter. Historically, in the radiographic era, bowel and bladder structures were dose-limiting organs at risk. Few retrospective studies from this period have mainly focused on severe (G3 or higher) vaginal morbidity, with the aim to establish a maximum tolerance dose. No dose volume response relationship for vaginal morbidity has been established so far. ABSTRACT OVERVIEW: The aims of this analysis are: 1. to report on the vaginal morbidity, including single 54 AWARDS | 2ND ESTRO FORUM - REPORT endpoints of vaginal dryness, stenosis, mucositis, bleeding, fistula and other vaginal symptoms (reported in free text field) during the first two years of follow-up, in the ongoing EMBRACE study 2. to establish a dose response relationship. As no specific vaginal dose points or contoured volume of the vagina were assessed in the EMBRACE study, the ICRU rectal point was chosen as most representative surrogate marker for the delivered dose to the upper part of the vaginal wall, because of its close proximity and its defined relation to the vaginal wall and the applicator. of image guided adaptive brachytherapy, serves as a promising starting point for future research. These results have led to the initiation of a vaginal sub-study, which has started accrual in the frame of the ongoing EMBRACE study. This research project refines the assessment of vaginal side effects and dose assessment in more specific vaginal points as well as patient reports about the impact on sexuality. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? This approach will provide more precise information with regard to the dose effect relationship of vaginal morbidity, which can be taken into account during treatment optimization, i.e. with appropriate vaginal sparing techniques. The overall goal is to reduce the dose to the non-involved vagina in order to decrease these side effects and improve patients’ quality of life. With the possibility of dose adaption and optimization in IGABT, a highly individualized and tailored treatment has become possible, comparable to the targeted therapies in medical oncology (“personalized medicine”). WHAT WERE THE MAIN FINDINGS OF YOUR RESEARCH? Severe G3/G4 vaginal morbidity is rare, whereas the majority of patients are likely to experience mild to moderate (G1/G2) vaginal morbidity in the first two years after end of treatment. Most frequently reported symptom is vaginal stenosis (narrowing and/or shortening of the vagina). 1. With increasing dose to the ICRU rectal point, the probability for vaginal morbidity G≥2 increases significantly (p=0.002). 2. With increasing dose to the ICRU rectal point, the probability for vaginal morbidity G≥2 increases significantly (p=0.002). WHAT IMPACT COULD YOUR RESEARCH HAVE? The main impact of this interim report is to raise awareness for the high frequency of mild to moderate vaginal morbidity. In addition, a dose response relationship to the ICRU rectal point is shown, which can be easily and reproducibly assessed in patient images both with the use of MRI/CT and radiographs. The fact that a single point shows already a dose response effect within the framework Figure 1 Dose response curve: Increasing dose to the ICRU rectal point (“recto-vaginal point”) was associated with higher frequency of G≥2 vaginal morbidity (p= 0.002). Patients were grouped according to 5Gy intervals for better illustration; mean and standard deviation are shown. 2ND ESTRO FORUM - REPORT | AWARDS 55 4 ESTRO - JACK FOWLER UNIVERSITY OF WISCONSIN AWARD 2013 This Award is conferred upon the best abstract in the field of radiation physics or radiation technology, BEYOND VMAT - HIGH SPEED DELIVERY OF ROTATIONAL IMRT WITH CONE-BEAM TOMOTHERAPY By Benjamin Sobotta Section for Biomedical Physics, University Clinic for Radiooncology, Tuebingen, Germany CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: The fastest way to deliver photon radiotherapy arguably uses a rotating, modulated beam. Today’s treatment machines are not optimised for this type of delivery. This study aims to explore the quality and efficiency of radiotherapy treatments if these technological constraints are removed, and replaced by a realistic, optimized design. ABSTRACT OVERVIEW: This study investigates the optimum design of a treatment machine for intensity-modulated radiotherapy that allows the fastest possible treatment delivery without reducing quality compared with the current state-of-the-art. The treatment machine was realistically modelled using a dose-optimisation software. A variety of parameters, such as beam rotation speed, collimator speeds and dose rates were analysed. The most favourable design is a continuously rotating beam with a high rotation speed and a delivery in 5-12 full rotations (compared to 1-2 today). This allows the delivery of high-quality treatments about 3-5 times faster than today. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? 1. The current design of treatment machines is not optimum for the fast delivery of rotational intensity-modulated therapy. 2. The optimum design is a continuously rotating, modulated cone-beam with a high rotation speed. 3. This delivery mode allows the application of higher degrees of beam modulation in multiple passes of the beam over the same angle than is currently possible. 56 AWARDS | 2ND ESTRO FORUM - REPORT WHAT IMPACT COULD YOUR RESEARCH HAVE? A dedicated treatment machine for rotational intensity-modulated radiotherapy would allow very fast delivery of treatments, thereby greatly reducing the risk of patient movement and increasing patient comfort during irradiation. With overall treatment times of less than 1 minute, even in complex situations, treatment uncertainties caused by involuntary patient or organ movements would be virtually eliminated. IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? The technological advancement in radiotherapy enables a much higher precision of dose delivery and thereby a lower complication profile or more radical treatments, such as stereotactic body radiotherapy. Driving forces of this development are imaging of the patient in the treatment position which allows repositioning of the target to the precise treatment location, and rapid treatment delivery, which reduces treatment uncertainties and patient discomfort. This study proposes a design for treatment machines which would further reduce irradiation time to an extent, that it would be the shortest component of the treatment. ESTRO 4 - 8 April 2014 Vienna, Austria 5 GEC-ESTRO BEST JUNIOR PRESENTATION SPONSORED BY NUCLETRON This Award is dedicated to ESTRO’s in-training members or members who are under 36 years of age. The winning abstract was selected by the GEC-ESTRO-ISIORT Europe meeting experts. MOTION SIMULATIONS WITH A STATISTICAL DEFORMATION MODEL TO EVALUATE PTV MARGINS IN LOCALLY ADVANCED PROSTATE CANCER By Isabelle Kindts Department of Radiation-Oncology, University Hospital Leuven, Belgium CONTEXT OF THE STUDY / PRELIMINARY INFORMATION: Whole breast radiotherapy followed by a boost irradiation to the tumour bed is the standard treatment after breast conserving surgery for early stage breast cancer patients. Different techniques exist to perform a radiotherapy boost. We compared three different boost techniques in terms of local and loco-regional recurrences and overall survival. ABSTRACT OVERVIEW: The aim of the study is to compare three different radiotherapy boost techniques in women with early stage breast cancer treated with breast conserving therapy (breast conserving surgery followed by whole breast radiotherapy), in terms of differences in local and loco-regional recurrences and overall survival. From 2000 to 2005, 1381 patients were treated in our department with breast conserving therapy for invasive breast cancer. An electron boost was performed for a superficial boost volume (less the 29 mm under the epidermis), in all other cases a brachytherapy boost was proposed. When patients refused or a brachytherapy boost was not possible because of technical reasons, a photon boost was performed. WHAT WERE THE THREE MAIN FINDINGS OF YOUR RESEARCH? 1. No significant differences were found between the three boost techniques with respect to local and loco-regional recurrences. Five- and 10-years relapse free survival rates were 98.8% and 96.9%. (figure 1) 2. No significant differences were found between the three boost techniques with respect to overall survival. Five- and 10-years overall survival rates were 95.1% and 86.2%. (figure 2) 3. The metastasis-free survival was longer in the electron boost group (90.7% at 10 years) and the brachytherapy boost group (87.3% at 10 years) than 58 AWARDS | 2ND ESTRO FORUM - REPORT in the photon boost group (82.7% at 10 years). This difference was not significant anymore after correction for tumour stage (pT) (p=0.09) and lymph node stage (pN) (p=0.1). (figure 3) Figure 1 WHAT IMPACT COULD YOUR RESEARCH HAVE? We demonstrated very low local and loco-regional recurrences at 10 years in patients treated for invasive breast cancer with breast conserving therapy followed by a boost irradiation to the tumour bed. No difference in recurrence was observed comparing the three different boost techniques. These observations indicate that the selection criteria for the boost modality used in our department are valid. It would be interesting to validate our results in a prospective, multi-centric study. The results of this study can be used to evaluate the results of newer boost techniques in breast radiotherapy, such as Simultaneous Integrated Boost (SIB) or intra-operative boost. Figure 2 IS THIS RESEARCH INDICATIVE OF A BIGGER TREND IN ONCOLOGY? This study has demonstrated excellent results with wellknown techniques and strict guidelines. In the last decade, sophisticated and complex techniques in breast radiotherapy, such as partial breast irradiation, IMRT, arc therapy etc, are booming. We should be aware that implementing new techniques can only be defended in the presence of strong evidence of improved outcome. Furthermore, in each department the performance of new techniques should be compared to the standard technique as well as to data in the literature. Figure 3 2ND ESTRO FORUM - REPORT | AWARDS 59 THANK YOU TO... ESTRO would like to thank the authors of the abstracts for taking the time to answer our questions about their work, the chairpersons of the congress and of the scientific committees for having selected the most outstanding abstracts and introducing each section, and also to Anne Hansen Ree, Fiona Stewart, Ann Barrett, Michelle Leech and Brendan McLean, who together with the Chairs took the time to review the content of this report.. A special thank you goes out to the National Organising Committee chairs, Jacques Bernier, Raymond Miralbell and Raphaël Moeckli for having gracefully accepted to host the 2nd ESTRO Forum. CONTACT ESTRO Rue Martin V, 40 1200 Brussels - Belgium Tel.: +32 2 775 93 40 [email protected] www.estro.org