CONFIDENTIAL Master Thesis Optimisation of Treatment Time in Ultrasound guided High Intensity Focused Ultrasound (HIFU) in the Treatment of Breast Fibroadenomata. Mirjam Peek, BSc Master Thesis Technical Medicine Faculty of Science and Technology December 5th, 2014 Optimisation of Treatment Time in Ultrasound guided High Intensity Focused Ultrasound (HIFU) in the Treatment of Breast Fibroadenomata. By Mirjam Peek, BSc S0200441 Master Thesis Technical Medicine Faculty of Science and Technology [email protected] [email protected] Graduation date: December 5th 2014 Graduation Committee: Chairman: Prof. Wiendelt Steenbergen [email protected] Medical Supervisor: Dr. Mr. Michael Douek [email protected] Technical Supervisors University of Twente: Dr. Ir. Bennie ten Haken [email protected] Guy’s hospital: Dr. Muneer Ahmed [email protected] External Supervisor: Dr. Srirang Manohar [email protected] Process Supervisor: Drs. Paul van Katwijk [email protected] THIS THESIS AND THE INFORMATION IN IT ARE PROVIDED IN CONFIDENCE AND MAY NOT BE DISCLOSED TO ANY THIRD PARTY OR USED FOR ANY OTHER PURPOSE WITHOUT THE WRITTEN PERMISSION OF THE AUTHOR UNTILL DECEMBER 5TH 2015. ii Preface In December 2013 I started my Technical Medicine graduation on the HIFU-F project at Guy's and St. Thomas' hospitals after a previous three month internship in London. This thesis reports the results of the work I performed in the last 12 months for the master in Technical Medicine. Firstly, I would like to thank my medical supervisor, Michael Douek, for giving me the opportunity to do my graduation in London. You trusted in me and gave me the responsibility of co-running the HIFU-F trial. You challenged me to get the best out of me and this resulted in three articles, three oral and three poster presentations and a Young Investigators Award. I am looking forward in working with you in the next three years during my MPhil/PhD. I would like to thank Muneer Ahmed for his supervision and support during the last 12 months. I was always able to go to you for advice and/or questions and you gave me insight in what is possible in the future. The trial started with a lot of struggles but we managed to overcome all obstacles and worked out a steady procedure. Bennie ten Haken, thank you for the support and advice during my graduation. You made me look at situations from a different perspective which made it easier for me to solve the problem or handle it better. I would like to thank you for the advice you gave me on the future perspective of me as a Medical physician. I would like to thank Paul van Katwijk and my supervision group (Richte Schuurmann, Gert-Jan Snel and Jordy van Zandwijk), for the useful monthly feedback meetings. Looking back has made me realise how far I have gotten and how much I have learned in the last year. I have learned to be proud of my accomplishments and not to take everything for granted. You gave me advice when I was doubting about my future in Technical Medicine and made me realise that there are more possibilities, it takes just one person to step up as a pioneer. As a result, and with the advice given by Bennie ten Haken, I managed to get in contact with the MST about arranging a Clinical Fellowship at their breast department. I would like to thank Wiendelt Steenbergen and Srirang Manohar for accepting to be my chairman and external supervisor for this assignment. Even though we did not have much contact, I would like to thank you for the support during this period. And last but not least, I would like to thank the patients for participating in the trial, without them this thesis would not have been possible and we would not have had these results. Finally, I would like to thank my family, friends (both in London and in the Netherlands), colleagues and housemates for their support during the last year. You all created a safe environment in which I was able to work on this project fulltime and you made me realise that relaxing every now and then is important as well and you played a great part in this. Without all the people mentioned above this thesis would not have been made possible. iii Abstract Introduction Breast fibroadenomata (FAD) are the most common breast lesions in woman. High intensity focused ultrasound (HIFU) is a promising non-invasive ablative technique for the treatment of these FAD. In HIFU, an ultrasound (US) beam propagates through tissue as a high-frequency pressure wave elevating the temperature within a few seconds without causing damage to the direct adjacent tissues. Two systematic reviews were performed evaluating the current evidence of HIFU and minimally invasive ablative techniques in the treatment of breast cancer. In the "HIFU in the treatment of breast Fibroadenomata" (HIFU-F) trial, circumferential HIFU treatment was performed to isolate the FAD from its blood supply. Outcome measures were volume decrease on US, short-term complication rate, decrease in treatment time and patient recorded outcome measures. Methods Two systematic reviews were conducted following the Cochrane Handbook and STROBE statement. Patients (age ≥ 18 years) were recruited with symptomatic palpable FAD which had to be visible on US (graded either benign or indeterminate). Patients were treated using the US- guided - Echopulse device (Theraclion Ltd, Malakoff, France) under local anaesthesia. Two circumferential rings of pulses were applied by deselecting the centre of the FAD. Patients were followed-up at two weeks, three, six and 12 months. Results The systematic review demonstrated that very small studies have been conducted to HIFU and other ablative techniques. From December 2013, 25 patients with symptomatic palpable FAD underwent circumferential HIFU treatment. Nine patients opted for HIFU due to pain or discomfort. Average treatment time was 38.5 minutes (SD 12.0 minutes). Circumferential treatment significantly reduced treatment time by an average of 36.4% (SD 18.9%) (T-test, P=0.0001, two tailed). At two weeks short-term complications were erythema (n=6), ecchymosis (n=8), numbness of the skin (n=1), hypo-pigmentation (n=1), dimpling of the skin (n=1), a first- degree skin burn (n=1) and reduced pain in 5/8 patients with resolution in two patients. At three months all local complications had resolved apart from hyper-pigmentation (n=6). Reduction of pain was seen in 7/8 patients with resolution of pain in six. Two weeks post-treatment a volume reduction of 14.3% (SD 24.9%) was seen on US and at three months the reduction was 41.7% (SD 28.6%). Conclusion Circumferential HIFU ablation of FAD is feasible with a significant reduction in treatment time. Further patient follow-up and large prospective trials are needed to demonstrate consistent tumour and margin necrosis, reliable follow-up imaging and establish the effect of HIFU treatment. iv Table of Contents Optimisation of Treatment Time in Ultrasound guided High Intensity Focused Ultrasound (HIFU) in the Treatment of Breast Fibroadenomata. ............................................................................... ii Graduation Committee: ............................................................................................................................. ii Preface ...................................................................................................................................... iii Abstract...................................................................................................................................... iv Table of Contents ........................................................................................................................ v Table of Figures and Tables ..................................................................................................... viii List of Abbreviations ................................................................................................................... ix 1. Introduction ............................................................................................................................ 1 1.1 Fibroadenomata .................................................................................................................................. 1 Diagnosis ............................................................................................................................................... 1 Management ......................................................................................................................................... 2 1.2 Breast Cancer ...................................................................................................................................... 3 1.3 Ablative Techniques ............................................................................................................................ 4 1.4 Aim of Thesis ....................................................................................................................................... 6 2. Systematic Review: High Intensity Focused Ultrasound (HIFU) Ablation in the Treatment of Breast Tumours ......................................................................................................................... 8 2.1 Material and Methods .......................................................................................................................... 8 Study selection .....................................................................................................................................