MODERN RADIATION ONCOLOGY: ECONOMICAL ASPECTS AND INNOVATIONS IN THE TREATMENT

September 14-15, 2012 PALANGA INTERNATIONAL CONFERENCE MODERN RADIATION ONCOLOGY: ECONOMICAL ASPECTS AND INNOVATIONS IN THE TREATMENT ORGANISERS: LITHUANIAN SOCIETY FOR RADIATION THERAPY INSTITUTE OF ONCOLOGY VILNIUS UNIVERSITY 1

one of the mains goals of International conference Modern radiation oncology: Economical aspects and innovations in the treatment was to give the newest information for medical society about the achievements in Radiation Oncology, Oncological diagnostics, relation clinics with science. The perfect location, good quality of lectures, nice atmosphere made possible to share news and feel comfortable. It was also an opportunity for the young professionals to meet, learn and deepen their engagement with Radiotherapy society. 2 3

Institute of Oncology, Vilnius University Director Prof. Konstantinas Povilas Valuckas Dear colleaques, Lithuanian Society for Radiation Therapy President dr. Ernestas Janulionis The number of audience and quality of speakers, per- I am very delighted with the past conference held in haps, was the most important part of the conference Palanga. Although its impossible to cover all aspects of in Palanga. But it was also good to see old friends and Radiation Oncology in two days, but the sections were colleagues, at the same to get opportunity to make new covering various aspects of Radiation Oncology (con- friends. This is also very important part of our hard job, centrating on two main locations-ca prostate and Ca our life. Conference was very successful, gathering,as cervix uteri), the role of newest technologies in diag- mentioned,not only outstanding speakers, but also wide nostics, some socioeconomical aspects of cancer care, variety of physicians(radiation oncologists, surgeons, which is becoming a burden for developing countries, GMP), Medical physicists, scientists from different fields. as well as for developed, including presentations about integrity of science and clinics. During last decade our Such conference its not only possibility to educate auditory from local became international, including well Radiation Oncologists, but also moves seeking interin- known lectures from leading Cancer centers in differ- stitutional and international cooperation, for effective ent countries. This also shows that Lithuanian Radiation common works and projects, for developing of scientific Oncologists are recognized as equal partners in profes- work in international field. sional level. Organizing committee thanks for everyone who attended conference, for every lecturer, for all who made I want to thank for everyone and wish a good luck in professional field and personal life. 4 us possible to meet in our wonderful Palanga-to work, to relax, to enjoy 5

Penktadienis, rugsėjo 14 d. / Friday, September 14 9.00-10.00 Dalyvių registracija. Kava Registration. Coffee. 10.00-10.15 Konferencijos atidarymas. Sveikinimo kalba. Vilniaus universiteto Onkologijos instituto direktorius prof. Konstantinas Povilas Valuckas Conference opening. Welcome address by IOVU Director prof. Konstantinas Povilas Valuckas 10.15-14.00 Plenarinis posėdis: Socioekonominiai vėžio gydymo aspektai. Šiuolaikinė spindulinė terapija. Socioeconomics of the cancer care and modern radiation therapy Moderatoriai - K.P. Valuckas, E. Juozaitytė, V. Atkočius, E. Janulionis 10.15-10.30 V. Atkočius E. Janulionis (Vilnius, Lithuania) Lietuvos spindulinės terapijos infrastruktūra 1999-2011 Infrastructure and costs of radiation oncology in Lithuania 1999-2011 10.30-11.00 R. Sullivan (London, UK) Can we really deliver affordable cancer care in the next decade? 11.00-11.30 B. McCormick (New York, MSKCC, USA) Stereotactic body radiation therapy (SBRT) 11.30-12.00 L. Kepka (Warsaw, Poland) Stereotactic radiotherapy in brain tumors 12.00-12.30 A. P. Gerbaulet-Le Gaonach (Paris, France) The history of brachytherapy: from Radium to HDR 12.30-12.40 Kavos pertrauka (Coffee break) 12.40-13.00 E. Juozaitytė (Kaunas, Lithuania) Krūties navikų biologinio heterogeniškumo įtaka lokalaus gydymo sprendimams The influence of biol ogical heterogeneity of breast tumors to local treatment decisions 13.00-13.30 F. Lagerwaard (Amsterdam, Netherlands) Early stage NSCLC: Is surgery still the standard of care? 13.30-14.00 B. Engels (Brussel, Belgium) Dosimetric and clinical capabilities of the TomoTherapy System in a daily practice 6 14.00-14.30 Pietūs (Lunch) 14.30-16.50 Prostatos vėžio diagnostika ir kombinuotas gydymas Diagnostics and combined treatment of prostate Cancer Moderatoriai - M. Jievaltas, A. Ulys, D. Norkus 14.30-15.00 F. Sedlmayer (Salzburg, Austria) Newest achievements in prostate cancer radiotherapy 15.00-15.30 P. Tonhauser (Berlin, Germany) The IsoCord Prostate Implant System from Bebig 15.30-15.45 A.Ulys (Vilnius, Lithuania) Priešinės liaukos vėžio ankstyvos diagnostikos programų nauda Cost benefit of early prostate diagnostic programs 15.45-16.00 S. R. Letautienė, R. Grigienė, R. Briedienė (Vilnius, Lithuania) Prostatos vėžio MRT diagnostika MRI diagnostics in prostate cancer 16.00-16.15 M. Jievaltas (Kaunas, Lithuania) Didelės rizikos grupių priešinės liaukos vėžio operacinio gydymo galimybės Possibilities of surgical treatment in high risk prostate cancer 16.15-16.30 L. Jaruševičius (Kaunas, Lithuania) Didelės dozės galios prostatos navikų brachiterapija galimybės ir apribojimai HDR prostate brachytherapy-possibilities and limits 16.30-16.50 D. Norkus, K.P. Valuckas (Vilnius, Lithuania) Priešinės liaukos vėžio hipofrakcionuota spindulinė terapija VUOI patirtis ir vykdomi tyrimai Prostate cancer hypofractionated radiation therapyexperience of IOVU and current trials 16.50-17.30 Diskusija: D. Norkus, A. Ulys, M. Jievaltas, L. Jaruševičius Didelės rizikos priešinės liaukos vėžys gydymo taktikos parinkimas Discussion: High risk prostate cancer- the choice of treatment 17.30-18. 30 Lietuvos Spindulinės Terapijos Sąjungos prezidento ir Tarybos rinkimai 19.00-23.00 Vakaronė viešbutyje Gabija Šeštadienis, rugsėjo 15 d. / Saturday, September 15 9.00-11.15 Gimdos kaklelio vėžys Cancer of cervix uteri Moderatoriai - A. Inčiūra, Ž. Gudlevičienė 9.00-9.15 R. Grigienė (Vilnius, Lithuania) Gimdos kaklelio vėžio MRT diagnostikos galimybės Development of MRI diagnosis in cervix cancer 9.15-9.30 V. Rudaitis (Vilnius, Lithuania) Ar tikslingas vietiškai išplitusio gimdos kaklelio vėžio chirurginis gydymas? Is it reasonable to treat surgically locally advanced cervical cancer? 9.30-9.45 A. Inčiūra (Kaunas, Lithuania) Gimdos kaklelio vėžio brachiterapijos optimizavimas The optimization of cervical cancer brachytherapy 9.45-10.00 K.P. Valuckas, E. Janulionis, V. Atkočius (Vilnius, Lithuania) Atokūs Cf-252 gama neutronų brachiterapijos taikymo gimdos kaklelio IIB ir IIIB vėžio spindulinėje terapijoje rezultatai Long-term results of Cf-252 gamma neutron brachytherapy in treatment of cervix uteri IIB and IIIB stages 10.00-10.30 J. Lyczek (Brzozow, Poland) Brachytherapy in Poland 10.30-11.00 P. Tonhauser (Berlin, Germany) The HDR Multisource System from Bebig An Innovation with large clinical experience 11.00-11.15 D. Kanopienė (Vilnius, Lithuania) Sergančių gimdos kaklelio ikivėžinėmis ligomis ir vėžiu bei gimdos kūno vėžiu mikrosatelitinio nestabilumo tyrimai Microsatellite instability in cervical and corporis uteri cancer 11.15-11.30 Kavos pertrauka (Coffee break) 11.30-15.15 Įvairūs spindulinio gydymo aspektai Different aspects of radiation therapy Moderatoriai - E. Aleknavičius, A. Plieskienė 11.30-12.00 A. P. Gerbaulet-Le Gaonach (Paris, France) Brachytherapy in penile carcinoma 12.00-12.30 B. McCormick (New York, MSKCC, USA) Partial breast irradiation 12.30-12.45 A. Plieskienė (Klaipėda, Lithuania) Širdies ligos po adjuvantinio kairės krūties vėžio spindulinio gydymo Radiation induced heart morbidity after adjuvant radiotherapy for left breast cancer 12.45-13.00 O. Utehina (Ryga, Latvia) Deep inspiration breath hold treatment based technique 13.00-13.30 B. McCormick (New York, MSKCC, USA) A prospective randomized trial for good risk ductal carcinoma in situ (DCIS), comparing radiation (RT) to observation (OBS) 13.30-13.45 Kavos pertrauka (Coffee break) 13.45-14.00 V. Rudžianskas (Kaunas, Lithuania) Galvos ir kaklo srities navikų atkryčio gydymas didelės dozės galios brachiterapija Treatment of head and neck tumors relapses with HDR brachytherapy 14.00-14.30 R. Rotomskis (Vilnius, Lithuania) Nanotechnologijų galimybės navikų terapijoje Possible applications of nanotechnologies in cancer therapy 14.30-14.45 V. Kulvietis,V. Karabanovas, A. Jagminas R. Rotomskis (Vilnius, Lithuania) Magnetinių nanodalelių panaudojimas vėžinių darinių MR vaizdinime ir terapijoje Application of magnetic nanoparticles in MRI and treatment of cancer 14.45-15.00 K. Sužiedėlis (Vilnius, Lithuania) Molekuliniai žymenys individualizuotai spindulinei terapijai: mitas ar realybė Molecular biomarkers for the individualized radiotherapy: myth or reality 15.00-15.15 D. Adlienė, J. Laurikaitienė (Kaunas, Lithuania) Apšvitos dozių vertinimas galvos ir kaklo navikų brachiterapijoje Evaluation of exposure doses in head and neck brachytherapy Konferencijos uždarymas ir pietūs Conference closing and Lunch 7

Ploquin N.A. et al., 2008 (metaanalysis) cost of 1 treatment course ~ 3239 ± 566 INFRASTRUCTURE OF RADIATION ONCOLOGY IN LITHUANIA 2000-2011 ERNESTAS JANULIONIS VYDMANTAS ATKOČIUS, ERNESTAS JANULIONIS Institute of Oncology, Vilnius University INTRODUCTION History of Radiation Oncology starts in Lithuania in third decade last century. Till 1997 Radiation centers were equipped with less effective, bulky devices. MATERIALS AND METHODS The ESTRO Questionnaire regarding radiotherapy infrastructure was sent to the Lithuanian radiotherapy centers. 50 % replies were received. RESULTS From mentioned data the picture changed we ride off Co-60 units getting linear accelerators, modern brachytherapy machines, simulation and treatment planning devices. Total number at the moment: Linacs-10, brachytherapy units-5, simulators-5. Increase in Linacs per 1 million populations is 5 folds during the 10 yr period. 8 from 10 Linacs are younger than 5 years. In com- VYDMANTAS ATKOČIUS parison with ESTRO and USA recommendations pts treated per Linacs number is much higher in Lithuania. Different picture pts treated by brachytherapy twice less in Lithuania than EU. Load of pts per Radiation Oncologist and Medical Physicist quite comparable with other countries. The staff cost per patient in Lithuania grew up almost five times but still is four-six times less than in Sweden and EU. The most costly part of Radiation Therapy in Lithuania is equipment 52 % (in comparison Sweden 20 %). Cost of RT per patient in Lithuania is 4-5 times lower than other countries of EU. Lithuania, 2000 % Lithuania, 2011 % Belgium, 2000 % Belgium, 2009 % Sweden, 2000 % Finland, 2000 % Personnel costs 43 34 50 51 51 37 Equipment costs 39 52 30 33 20 40 Space costs 5 1 3 9 6 9 Material costs 3 3 4 4 11 6 Overhead costs 10 10 13 3 12 8 Distribution of RT resource costs across different types of inputs (%) ESTRO recommendation Lithuania, 2011 Sweden, 2000 Australia, 2006 Medical phys. per 1 Linac 1 1,4 1,1 1,7 Pts. per 1 radiation oncologist per yr. 200-250 198 322 249 Pts. per 1 medical physicist per yr. 450-500 220 300 293 Radiation technologists per 1 treatment unit 2/ treatment unit 2,6/ treatment unit 6/ treatment unit - CONCLUSIONS Lithuanian radiotherapy has major changes in equipment, staffing and substantial material supply. What we need? More specialized Linacs, implementation of newest RT methods, more workload for brachytherapy unit. Cost of RT per patient (2005, EUR) 5000 4000 3000 2667 3265 4029 3668 2877 2723 2000 817 1000 0 8 UK Canada Sweden Australia Belgium USA Lithuania, 2011 9

Major structural changes to society. People don t just get cancer multiple effects on cost Can we really deliver affordable cancer care in the next decade? R. Sullivan R. Sullivan (London, UK) Source: Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat, World Population Prospects: The 2006 Revision and World Urbanization Prospects What are the cost drivers? The evolution of man and cancer costs Macro-economic Socio-Demographic Techno-Cultural Trade-offs with survival and reproduction: what matters is reproduction not healthy ageing! Mismatch: our evolutionary adaptive environment has made us like fat / sweet but this is now a risk factor in our modern environment. Globalisation of cancer risk factors is a major concern Ecology of cancer rests on the social determinants of health. We have failed to manage the negative health consequences of development Purushotham A & Sullivan R. Darwin, medicine and cancer. Annals Oncol 2010, 21: 199-203 Source: United Nations, World Population Prospects: The 2008 Revision (medium scenario), 2009. Trend from high income countries. The world in 1950. Hughes & Hunter. Disease and Development in Africa. Soc Sci Med 1970: 443-93 Cultural attitudes towards health are deeply ingrained: we love consuming healthcare (1) David Doller. Is globalisation good for your health? Bull WHO 2001, 79: 827-33. (2) David Woodward et al. Globalization and health. Bull WHO 2001, 79: 875-81. Drive to seek new medicines and novel treatments (neophilia) is very strong By 2012 pharmaceutical spend will have reached $929 billion 65% of global population, however, relies on traditional medicine Massive social costs in both developed and developing countries - in the latter between 40-81% of medicines are funded out-of-pocket. Sullivan R, Behncke I, Purushotham A, Why do we love medicines so much? An evolutionary perspective on the human love of pills, potions and placebo. EMBO Reports 2010, 11(8): 1-7. The world in 2009. So, we are seeing huge population ageing effects plus. 25 1980 2010 8 World 10 16 15 14 5 2040 3 3 Africa 6 7 4 7 Success of research is also a major cost driver 624 new cancer medicines being tested in clinical trials in Europe & USA.. Result of this is more and more spend on cancer technologies such as medicines (Global sales ($M) 2007-2012) 16 8 4 Asia Latin America and the Caribbean More Developed Regions 11

But how can you deliver fair affordable cancer treatment when the world we live in now is so different? Understanding the societal value of innovation beyond the cost paradigm Value of new technologies in cancer is based on perception of them as having the power to heal (1). New medicines may facilitate further fundamental research and/or drive further development. They may be important for the general zeitgeist of development in this area (2). Stereotactic body radiation therapy (SBRT) B. McCormick (New York, MSKCC, USA) (1) Sjaak van der Geest et al. The charms of medicine. Med. Anthropol. Quart. 1989, 3(4): 345-67. (2) Peter Drahos. Trading in public hope. Annals, AAPSS. 2004, 592: 18-38 Politicians also have to manage all non-communicable diseases, why should cancer be given special treatment? Fundamental tension(s) over how to solve the cost crisis : multiple lessons Accurately measure costs & link to outcomes, Robert Kaplan & Michael Porter, Sept, 2011 Harvard Business Revew Implement Value Based Pricing Make it harder to get a new technology into routine care Reduce / stop the use of unproven cancer technologies Absolute requirement for economic studies in all clinical research Human desire for health services MSKCC Update: Where We Are Now Dose escalation 2003-2005 (1800-2400cGy) Extensive disease (ie circumferential) received reduced doses <2400cGy All patients followed with serial imaging until death Local failure = radiographic progression What we really need to do for long term cost control is PREVENT Tobacco control Prevalence of overweight adults, USA 1992 Cancer costs of the future will be outside high income countries..if you think life is tough in the UK spare a thought for the cancer patient in Kenya. Low Dose High Dose (1800-2300cGy) (2400cGy) P N 413 80 333 Median Survival 16 months (278 months) 17 months (2-73 months) 15 months (2-78 months) 0.11 Resistant Histology Median GTV (cc) Median PTV (cc) Median GTV V100 72% 71% 72% 0.98 16cc 17cc (2-326cc) 16cc (8-367cc) 0.76 62cc 63cc (8-1107cc) 61cc (2-807cc) 0.20 93% 94% (75-100%) 92% (67-100%) 0.11 Summary All patients were treated with high quality plans In contrast to conventionally fractionated radiotherapy, traditional phenotypical factors such as histology and volume are not significant prognostic factors with high dose single fraction therapy Factors used in the analysis were well balanced Actuarial local control: 91% for high dose, 74% for low dose (p=0.0012) Cost of scaling up prevention would cost less than 1% of current healthcare spend yet we don t do it. Overall Discussion Number of events was low 2004 Patient Characteristics 413 lesions in 372 consecutive patients were treated with SRS 2003-2010 at MSKCC. 1800-2400cGy in a single fraction with LINAC based IGRT B. McCormick Dose of radiation is the only significant prognostic factor Radiosensitive and radioresistant histologies do equally well The dose of radiation is the only predictive factor for durable treatment success when utilizing high dose single fraction therapy Local tumor cures can be achieved at 2400cGy x 1 Radioresistant histologies in particular should be considered for high dose single fraction therapy Different mechanisms of response vs. conventional fractionation Scaling up action against non-communicable diseases: How much will it cost? WHO 2011 Threshold Effect for High Dose Radiosurgery The Ultimate Therapeutic Gain: Spine IGRT Improving the therapeutic ratio: Multimodality IGRT: The best of both worlds Reduce toxicity: Immune Response Significant reduction in volume of volume sensitive toxicity Reduce dose to dose sensitive toxicity Improve tumor control: Tumor dose is critical Tumor control at ~ 90% level regardless of tumor phenotype or size Greatest therapeutic gain may be for radioresistant disease 12

STEREOTACTIC RADIOTHERAPY OF BRAIN TUMORS L. Kepka L. Kepka (Warsaw, Poland) Stereotactic radiotherapy may be delivered in a single fraction as Radiosurgery (RS) or in a fractionated way as Fractionated Stereotactic Radiotherapy (FSR). Choice between RS and FSR is based mainly on the radiobiology of the lesion, size of the lesion, relation to the critical structures, preservation of function (f. ex.: hearing), and type of available technology. RS with use of single, ablative dose is suitable for small lesions, functional RS and when vessel s obliteration is a goal of treatment as in the case of arterio-venous malformations (AVM). Rapid dose fall-off (measured by conformity index and size of isodose of 10 or 12 Gy) and strict immobilization represent a pre-requisite for such techniques. FSR usually delivered via hypofractionation (f.ex. 5 x 5 Gy) is used for larger lesions or/and those located in the proximity of critical structures. Usually, the less strict immobilization (masques instead of stereotactic frame fixed to the skull) and linac-based treatment is used. Gamma-knife, in most cases, is using single fractions instead of FSR. Linac-based RS is equally effective as gamma-knife in 14 THE HISTORY OF BRACHYTHERAPY FROM RADIUM TO HDR A.P.GERBAULET-LE GAONACH (Paris, France) the treatment of brain metastases, as it was established in the prospective RTOG 95-08 trial. RS of brain metastases may be used as the exclusive treatment method or may be combined with whole brain radiotherapy (WBRT). It was shown in the prospective trial that addition of RS of single brain metastasis to the WBRT improves overall survival. No such effect was observed for RS of 2-3 metastases. On the other hand, the addition of WBRT to local treatment of brain metastases has no impact on survival. For that reason, omission of WBRT and intensification of local treatment is currently rapidly evolving trend in the approach to the management of brain metastases. The use of stereotactic treatment in radiotherapy of other brain lesions, as meningiomas, n. VIII schwannomas, AVM, and recurrent gliomas are presented during a meeting. Stereotactic radiotherapy of brain lesions is a high precision technique which should be used for small brain lesions when the exact tumor delineation is possible and healthy tissues sparing may be meaningful with its use. INTRODUCTION Since the first use of radium as a cancer treatment, more than one century ago, the evolution of brachytherapy is phenomenal. As written by the French philosopher Auguste Comte: Nous ne connaissons pas complètement une science sans la connaissance de son histoire (We don t completely know a science without the knowledge of its history). To tell this history will be presented in the first part the technical evolution of Brachytherapy divided in 7 chapters: historical data, radioactive sources, applicators-devices, remote afterloading machines, dosimetry, imaging, dose rates. In the second part the main indications of HDR brachytherapy are proposed, proposals based on some results. HISTORICAL DATA Main discoveries and Nobel Prizes: 1895 W.C.Roengen: X Rays, 1896 H.Becquerel: natural radio-activity, 1897 J.J.Thomson: electronsbeams, 1898 M.Slodowska-Curie radium. 1903 H.Becquerel, Marie and Pierre Curie: Nobel Prize for Physics. 1911 Marie Curie: Nobel Prize for Chemistry. During the first decade of the 20th century different treatments start using radium. 1901 Danlos and Bloc irradiated lupus (Paris), 1905 Abbe performed radium implants (USA). After the first war world the main schools were created: Institut du Radium (Paris), the Holt Radium Institute (Manchester), the Radium Hemmet (Stockholm), the Memo- A.P.GERBAULETLE GAONACH rial Hospital (New York) Progressively the bases of brachytherapy were established. 1914-1919 Stockholm and Paris methods for intracavitary radium therapy. During the 1930s Manchester System for interstitial implants (Paterson, Parker, and later Meredith) 1934 Discovery of artificial radioactivity by Pierre and Marie Curie s daughter, Irène Curie and her husband Frederick Joliot. Using artificial radionuclides a new era of brachytherapy was open. But unfortunately the qualities of radium were also exploited by some charlatans brachytherapy was presented as an universal treatment : arteriosclerosis, hemorrhoids, blenorragia, decreasing of virility Radioactive wool for babies, atomic soda, mean for destroying hairs. cream to stay young and beautiful, condom radium Nutex!! RADIOACTIVE SOURCES 1956-1969 a new era for brachytherapy entitled by the French school La curiethérapie moderne : artificial sources, manuel afterloading systems, remote control sources projectors, computerized dosimetry, and at the beginning of the 70 s definitive disappearance of radium in France. A series of slides shows different radionuclides according to dose rates: LDR iridium wires, caesium ; permanent implants seeds of gold, iodine, palladium ; PDR-HDR iridium, cobalt Studies comparing iridium vs cobalt for HDR demonstrate: no clinical difference 15

economical advantage in favor of cobalt, cost divided by a factor 5, but for cobalt the radioprotection (bunker ) needs to be higher. DEVICES-APPLICATORS 1) Interstitial brachytherapy Many kinds of devices, applicators have been employed, Ulrich Henschke was the first using, plastic tubes technique afterloaded with iridium. Some clinical examples of this very useful system are presented as well as other systems: guide gutters, hypodermic and guide needles, silk threads 2) Endocavitary brachytherapy Essentially in gynaecology (except mammosite) a lot of applicators manually loaded at the beginning and quickly switched with remote afterloading machines. Many examples will illustrate this chapter showing the evolution and the progressive sophistication. 3) Endoluminal brachytherapy Different applicator design must be elected according to tumour sites. REMOTE AFTERLOADING MACHINES It is difficult to describe all these machines: the first Curietron born in 1964 and nowadays modernized by Bebig, the Gynatron, the Amron, the Gamma Med; different projectors from Nucletron (Elekta), Varian (for interstitial, endocavitary, endoluminal brachytherapy), A specific presentation will describe the possibilities offered by Bebig. These remote afterloading projectors represent a very important progress: total radioprotection for personnel, choice of dose rates, treatment planning systems, dodimetry, reproductibility, optimization, DVH, automatic check step by step, quality assurance ROLE OF IMAGING Starting with the first tumoural volume evaluations progressively new radiological machines allow better and better knowledge of the tumour as well as the critical organs: classical-ray, ultra-sound, CT-scan, 16 MRI, PET scan To illustrate these possibilities some clinical examples are presented; the last one, for a soft palate cancer, showing better dose distribution with interstitial brachytherapy than CRT and IMRT. To conclude this chapter a slide from R.Poetter: What we need for brachytherapy guided by images illustrating the necessary tools and staff members. DIFFERENT DOSE RATES The irradiation is: continuous LDR (30-60cGy/h), fractionated MDR (140-180 cgy/h) and HDR ( >12Gy/h), hyper-fractionated PDR (0.5-1Gy/h), permanent Brachytherapy biological effects are closely depending on: total dose, dose/ fr., treatment duration, treated volume, dose distribution. The linear quadratic model (LQ) and the equivalence formula showing how to calculate difference between LDR and HDR. INDICATIONS OF HDR BRACHYTHERAPY. RESULTS In this second part we will try to focus on HDR brachytherapy. Fifteen years ago a meeting was organized in New-York: Brachytherapy in the next millennium. Two years later, as President of the French Society of Radiotherapy, I had the privilege to give the honorary conference: Quel avenir pour la curiethérapie? (What is the future of brachytherapy?). In France, during the last decade, the indications have evolved and progressively new dose rates are daily used. Many changes appear around the word. A very interesting study realized by F.Guedea shows the use of specific dose rates in European countries and also the main tumours treated with HDR brachytherapy. Three examples are rapidly developed: cervix, breast, prostate, for each one: treated protocols, doses, fractionation, results in term of survival, morbidity CONCLUSION In brachytherapy the change, the evolution, the progresses from radium to HDR is impressive, and it is not the end of the story! The situation has considerably evolved and carries on changing in all the fields of brachytherapy (sources, afterloaders, imaging, radiobiology ) as well as in other fields as diagnostic, therapeutic modalities without forgetting our better and better knowledge of each patient in term of genetics but also at the level of the tissue, of the cell, of the molecule. In all cases the role plays by computers is considerable. All these progresses allow the expansion of brachytherapy as a conservative treatment for selected patients with well adapted indications. Brachytherapy can be used alone or combined with other treatments. Combination external beam irradiation-brachytherapy are complementary tools allowing joint efforts to improve the patient care. One most important point is absolute and safety necessity to use a common language to be able to compare our results: patients to patents, institutes to institutes, articles to articles and nowadays this deep, essential work is far away to be achieved! Nowadays we can be seduced by all these attractive possibilities offered by the new brachytherapy but the role of the man have to stay essential! At the time of computerization in all fields, don t think that these marvelous machines are able to resolve all the patient problems. If you want to be a good brachytherapist you must be first a medical doctor; a straight daily collaboration with the physicists, with the companies is quite necessary but stay the conductor, in French chef d orchestre and for that it is necessary to well know the music!... THE INFLUENCE OF BIOLOGICAL HETEROGENEITY OF BREAST TUMORS TO LOCAL TREATMENT DECISIONS ELONA JUOZAITYTĖ Lithuanian University of Health Sciences Breast cancer mortality is decreasing thanks to early detection and improved treatment. However, the course of disease and prognosis after diagnosis of early stage of breast cancer are not always predictable. Recent genomic and molecular investigations have led to more comprehensive understanding of heterogeneity of breast cancer. Infiltrating ductal carcinoma can be separated into at least 5 molecular subtypes designated Luminal A- ER (+), PR(+/-), HER2/neu(-), Ki67 (<14%); Luminal B- ER (+), PR(+/-), HER2/ neu (-), Ki67 (>14%); Luminal B HER2- ER ELONA JUOZAITYTĖ (+), PR(+/-), HER2/neu (+); HER 2 overexpressing (ER-, PR-, HER2/neu (+); basal-like - ER(-), PR(-), HER2/neu (-), and CK5/6(+), EGFR(+), within triple negative ER(-), PR(-) and HER2/neu (-) each with different clinical outcomes. Breast cancer biology is very important in determining response to hormone therapy, targeted therapy and chemotherapy. But it is still unclear how tumor biology affects local treatment decisions and outcomes. The good news for patients is that the rate of local recurrence after breast conservation treatment with radiation has been declining and is relatively 17

low in contemporary practice. Estrogen/ progesteron receptor status and HER2/neu are well known as prognostic and predictive factors for determination of systemic treatment approaches. Patient age, margin status, lymphovascular invasion, tumor size, tumor grade, use of chemotherapy, and use of hormonal treatment were found to significantly impact local recurrence across multiple studies. Fewer data exist that the use of adjuvant trastuzumab reduced the risk of local-regional recurrence in HER2/neu positive tumors. Recent data have evaluated genomic signatures among node-negative, ER positive patients and it was reported that patients with a higher gene profile score had a higher risk for local recurrence. Recognition of the complexity of tumor biology suggests that breast cancer molecular subtypes correlate with outcomes of local-regional treatment. It was noticed that some molecular subtypes of breast cancer have higher local recurrence rates. Some authors raise the hypothesis that ER negative and triple-negative disease may be more radiation resistant biological subtypes than ER positive disease. ER positive, HER2/neu negative breast cancer correlate with low local-regional recurrence rates after adjuvant radiotherapy. However, triple-negative breast cancer has higher rates of local regional recurrence. There is increasing evidence that triple-negative breast cancer is associated with higher rates of local recurrence after breast conserving therapy and after mastectomy as well. Breast-conserving therapy remains an appropriate treatment option for patients with early stage, triple-negative disease. For such patients, it is reasonable to use chemotherapy, assure negative surgical margins and to add radiation boost to the primary tumor site after whole breast radiation. Early stage NSCLC: Is surgery still the standard of care? F. Lagerwaard 18 F. Lagerwaard (Amsterdam, Netherlands) 19

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and 2) Occasional influence on inter- and intrafractional prostate mobility and hence, implicaions on safety margin design. F. SEDLMAYER F. SEDLMAYER (Salzburg, Austria) Background: Permanent local tumor control after EBRT of prostate cancer has been shown to be a function of dose in every risk setting. Apart from the additional cytoreductive effect of antiandrogen medication, radiation doses above 76 80 Gy yield high local control rates even in advanced stages. To avoid excess morbidity in organs at risk, delivery of these dose ranges to a moving organ demand for utmost precision. Inter- as well as intrafraction prostate motion is a well documented phenomen, frequently compensated by larger PTVs, which might however be detrimental to normal tissue tolerance with special emphasis of the anterior rectal wall. Adaptive radiotherapy by modern means of image guidance was a breakthrough in likewise reducing PTV safety margins and the danger of geographic misses. Methods Among various methods of tracking the prostate during the course of a treatment, to date gold marker insertion turned out to be most feasible, serving as reference structures in EBRT planning, usually as 7-field step-and shoot IMRT. Integration of MRI into planning yields the best imaging of organ confinement. An innovative, autoadaptive correction strategy for prostate motions was developed at the Paracelsus University Clinic Salzburg, using direct MLC adaptation of IMRT segments with no couch movements required. Gold fiducials were 22 tracked in kilovolt and megavolt projections to determine interfractional translations, rotations, and dilations of the prostate. The markers were automatically detected in two pretreatment planar X-ray projections; their actual position in three-dimensional space was reconstructed from these images at first. The structure set comprising prostate, seminal vesicles, and adjacent rectum wall was transformed accordingly in 6 degrees of freedom. Shapes of IMRT segments were geometrically adapted in a class solution forward-planning approach, derived within seconds on-site and treated immediately. Intrafractional movements were followed in MV electronic portal images captured on the fly. For further rectal dose reduction, the potential of various spacer materials injected between prostate and rectum is under investigation. Spacers have shown to enlarge the distance towards the anterior rectal wall as most critical OAR structure. To date, different media are emergingly introduced, among them hyaluronic acid and PEG (polyethylenglycol) based media as well as water filled self-resorbing balloons. In a prospective matched-pair comparison, 60 patients are investigated. to compare two different spacer methods: amorphously shaped PEG (Space OAR) versus self-resorbing balloons (BIO Protect) versus a matched non-interventional group. Primary endpoints are: 1)Evaluation of the amount of achievable rectal dose reductions by method including the corresponding clinical morbidity Problem: Standard EBRT (70 Gy) Conclusion: We demonstrated the clinical feasibility of an online adaptive image-guided, intensitymodulated prostate protocol on a standard linear accelerator to correct 6 degrees of freedom of internal organ motion, allowing safe and straightforward implementation of margin reduction and dose escalation. Moreover, injection of rectal spacers might be the key to overcome rectal morbidity and open the window towards safe implementation of high-dose EBRT in hypofractionation. Strategies in primary RT Overall survival 100 Overall survival (%) OPTIMIZED EXTERNAL BEAM RADIOTHERAPY (EBRT) IN PROSTATE CANCER Results Between daily treatment fractions, 3D vector translations relative to skin markings were 9.3 +/-4.4 mm (maximum, 23.6 mm). Intrafractional movements in 7.7 +/- 1.5 min (maximum, 15.1 min) between kv imaging and last beam s electronic portal. There was a 10% probability of rotations >12 degrees, 5%>15 degrees(39 patients). Without rotational corrections, additional margins would have to account for this. Addressing intrafractional errors could further reduce margins to 3 mm. In an interim analysis after 28 patients, distensions of the anterior rectal wall could successfully be provided in all spacer patients. Spacers so far did not show a stabilizing effect on motion degree and direction between and during treatment fractions 80 Dose escalated / - intensified RT 60 70 Gy 40 20 0 Log-rank p < 0.0001 hazard ratio 0.51 0 1 2 [M. Bolla et al., Lancet 360:103-108,2002] 3 Number of patients at risk: 208 207 199 197 177 183 146 166 4 5 6 7 8 70 93 46 71 30 43 16 24 Optimization of simultaneous or consecutive systemic treatment Time since randomisation (years) 106 142 Does Dose matter? Kupelian, PA; Int J Rad Oncol Biol Phys 2004: Multi-Institution series on 2991 patients bned by treatment modality for unfavorable-risk pts. RP, EBRT <72 Gy, EBRT 72 Gy, PI, or COMB. Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials. Viani GA, IJROBP 2009 7 trials, 2812 pats. significant reduction of BF following high-dose (HD)RT (p<0.0001) in all risk situations < 72 Gy no difference in overall (p = 0.38) and cancer specific mortality rates (p = 0.45) More late Grade>2 GI toxicity HDRT should be offered to all patients, regardless of their risk status. 23

THE ISOCORD PROSTATE IMPLANT SYSTEM FROM BEBIG P. TONHAUSER P. TONHAUSER (Berlin, Germany) This presentation, provided by the Eckert & Ziegler Bebig GmbH, Berlin (Germany) described a state-of-the art prostate implant system (IsoCord). The importance of permantent Iodine-125 prostate implants as the best method for curing early prostate cancer state was highlited with specific focus on clinical outcomes and patient side effects. The Bebig IsoCOrd system, being introduced in 2012 in Vilnius, offers several advantages, like radiation protection for the application staff, fast and secure implantation of the 24 stranded seeds as well as stable seed positionioning inside the organ. The configuration of the IsoCord stranded seed chains allows the medical staff an easy way of configurating the seed length to the required length. It has also been pointed out that for logistical and customer support reasons the availability of production and company support in Europe (here Germany) might be of advantage. Keywords: Safety, Speed, Accuracy Cost benefit of early prostate diagnostic programs ALBERTAS ULYS, JONĖ VERIKAITĖ Institute of Oncology, Vilnius University In recent decades, the incidence of prostate cancer has grew in many countries. This fact was attributed to the spread of organized or opportunistic testing of prostatespecific antigen (PSA) levels in the blood serum of men. Due to the intensive PSA testing, prostate cancer is more often diagnosed at an early stage, and the incidence of advanced disease decreases over time. PSA screening saves lives [1] review, based on PSA screening conducted randomized studies : 1. The European Randomized Study of Screening for Prostate Cancer has published its 11-year follow-up results. Once again, they demonstrate that screening does significantly reduce death from prostate cancer. ERSPC screening study group found 40% of the less-advanced prostate cancer (with metastases) and 20% fewer prostate cancer deaths (mostly 55-69 m. Age limits) [2,3] 2. Prostate, lung, colorectal and ovarian (called Prostate, Lung, Colorectal, Ovarian, PLCO). PLCO study report revealed a significant impact on the mortality of men with little or no underlying disease. Prostate cancer-specific mortality was reduced by 44% (p = 0.03) [4] 3. Göteborg Randomized PopulationBased Screening Trial, Sweden reported Albertas Ulys 41% less advanced disease in screening group (> 66% of all tested men) and 44% reduction in prostate cancerspecific mortality (56% of all tested men). [5] In the 2006 the Lithuanian Prostate Cancer Early Diagnosis Program (LPCEDP) was launched. The LPCEDP provides a possibility for men to undergo PSA testing and urological examination for prostate cancer. In Lithuania mortality from prostate cancer in 2006-2010. changed only slightly. Most deaths from prostate cancer recorded in 2007. ( 589 cases). The incidence of prostate cancer declined in all age groups. LPCEDP increased incidence of stage II prostate cancer in 50-74 year-old men group. The most dramatic increase of stage II prostatae cancer was in 65-74 age men group. The incidence of stage III prostate cancer in Lithuania distinctly decreases in 65-74 year male group since 2008. (2009. established 331 cases, or 19.7% less than the year before).[6] Decrease in potentially deadly disease after four years of implementation LPCEDP, suggests that future mortality rates of prostate cancer will decline. Screening is necessary providing the prostate cancer patients the opportunity to offer all possible therapies as soon as possible. [7] 25

2011 PROSTATE CANCER STATISTICS SUMMARY (USA). Geographical distribution of incidence of prostate cancer 240,890 New Cases 33,720 Deaths a Year 92 Deaths a Day 4 Deaths an Hour 1 IN 6 MEN WILL BE DIAGNOSED WITH PROSTATE CANCER DURING HIS LIFETIME Score T2W Criteria 1 Uniform high signal intensity or heterogeneous transitional zone adenoma with well-defined margins 2 Linear or geographic areas of lower SI on T2W images 3 Intermediate appearances not in categories 1/2 or 3/4 4 Discrete, homogenous low signal focus/mass confined to the prostate 5 Discrete, homogeneous low signal intensity focus with extra-capsular extension /invasive behaviour or mass effect on the capsule (bulging) Score DWI Criteria 1 No reduction in ADC compared to normal glandular tissue. No increase in signal on any high b-value image ( b1000) 2 Diffuse, hyper intensity on b1000 image with low ADC; No focal features - linear, triangular or geographical features allowed 3 Intermediate appearances not in categories 1/2 or 3/4 4 Focal area(s) of reduced ADC but iso-intense signal intensity on high b-value images ( b1000) 5 Focal area/mass of hyper intensity on the high b-value images ( b1000) with reduced ADC Score DCE Criteria 1 Type 1 enhancement curve 2 Type 2 enhancement curve 3 Type 3 enhancement curve +1 For focal enhancing lesion with curve type 2 or 3 +1 For asymmetric lesion or lesion at an unusual place with curve shape 2 or 3 http://globocan.iarc.fr/ References: 1. Ramon Guiteras PSA Screening Saves Lives William J. Catalona M.D., Northwestern University, Chicago, USA. 2. What is new in PSA based screening for prostate cancer an Update of the ERSPC study Fritz H. Schröder on behalf of the ERSPC study group. 3. Schroder FH et al, NEJM 360:1320, 2009 4. Crawford ED et al. J. Clin Oncol 29:355, 2010 5. Huggson J et al Lancet Oncology 2010; 11:725-32 6. Robertas Adomaitis. Ankstyvos diagnostikos programos poveikio sergamumui priešinės liaukos vėžiu Lietuvoje vertinimas. Daktaro disertacija, Vilnius, LTU, 2012. 7. http://www.seer.cancer.gov PROSTATE MRI DIAGNOSTICS SIMONA RŪTA LETAUTIENĖ RŪTA BRIEDIENĖ, SIMONA RŪTA LETAUTIENĖ, RŪTA GRIGIENĖ Institute of Oncology, Vilnius University Accurate tumor staging is essential to determine appropriate treatment. Local stage can be evaluated by MRI: Extracapsular Extension (ECE) Seminal Vesicle Invasion (SVI) Bladder/Rectal Invasion Lymph Node Metastases Screening leads to 30-60% mortality re26 RŪTA BRIEDIENĖ duction, but PSA is unspecific, thus too many biopsies TRUS-Biopsy leads to overdiagnosis and under-grading. A more specific marker is needed, which could be multi-parametric MRI (T2 weighted image, Diffusion weighted image (DWI), post-contrast dynamic perfusion (DCE) image or spectroscopy (MRSI)). ADC value correlation on MRI difusion imaging with Gleason grade. The aggressiveness of prostate cancer can be evaluated according ADC value. (Hambrock, Radiology 2011) 27

Diffusion-weighted Imaging (DWI), and ADC map T3A prostate cancer in the left lobe with cancer spread to periprostatic adipose tissue. MINDAUGAS JIEVALTAS Lithuanian University of Health Sciences During last years more and more data are published concerning long term results of high risk prostate cancer surgical treatment. 5 year specific survival rates after radical prostatectomy are 93-99%, overall survivor 90-96%. Its really good data treating high risk cancer, which potentially can influence patients death in future. In our center data are similar-among 840 patients treated in 28 possibility that after surgery we will have so called disease in resected mass -it means, ability to achieve what we are seeking for. We have to mention that about half of the pts will need additional adjuvant treatment. We have to inform about it every high risk patient before surgery. So, according to literature data, radical prostatectomy is very effective way of local prostate cancer control. For few years European Urology and American Urology Associations have clear idea that for determined pts group (younger, less side diseases) in high risk prostate cancer radical prostatectomy is possible/necessary way of treatment. Emphasized that pts have to pass wide lymphadenectomy,they have to be warned about possibility of adjuvant treatment. References: Han M et al. Urol Clin North Am 2001;28:555-65. Ward JF et al. BJU Inter 2005;95:751-6 Briganti A et al. Eur Urol 2012;61:584-592 Milonas D, Smailyte G, Jievaltas M. Oncologic outcomes of surgery int3 prostate cancer: experience of a single tertiary center. Advances in Urology 2012: 8 T3B prostate cancer, with spread to seminal vesicles and periprostatic adipose tissu POSSIBILITIES OF SURGICAL TREATMENT IN HIGH RISK PROSTATE CANCER MINDAUGAS JIEVALTAS these pts we used adjuvant radiation therapy and/or androgen deprivation-combined treatment. Due to literature data25% of high risk patients in post-operative morphology had findings pt2(so called disease in prostate ). The prognosis for survival is very good. They don t need any additional treatment, disease stabilizes. For about 30% of pts pathomorphology answer pt3a+r0+no(so called disease in resected mass ). The survival rate for these pts is the same as pt2. So,almost every second patient who had only prostatectomy(monotherapy) has a chance to live without additional treatment. At this moment special pre-operative prognostic nomograms are proposed, by which is possible quite exactly calculate Lithuanian University of Health Sciences during 2002-2007 years 21% had locally advanced prostate carcinoma with other risk factors.5 years cancer specific survival rate for those pts was 94%, overall survival 90.7%. Risk factors for early biochemical disease progression in multifactor regressive analysis were p3b,n1,gleason 8-10. We want to stress that for a big part of HDR PROSTATE BRACHYTHERAPY POSSIBILITIES AND LIMITS LAIMONAS JARUŠEVIČIUS Lithuanian University of Health Sciences High-dose-rate (HDR) brachytherapy is used with increasing frequency for the treatment of prostate cancer. HDR afterloading brachytherapy in the management of localized prostate cancer has practical, physical, and biological advantages over low-dose-rate seed brachytherapy and external beam radiotherapy. There are no free live sources used, no risk of source loss, and since the implant is a temporary procedure following discharge no issues with regard to LAIMONAS JARUŠEVIČIUS radioprotection use of existing facilities exist. Patients with localized prostate cancer may benefit from high-dose-rate brachytherapy, which may be used alone in certain circumstances or in combination with external-beam radiotherapy in other settings. The purpose of this presentation is to present the essentials of HDR brachytherapy techniques along with the most important studies, that support their effectiveness in the treatment of prostate cancer. 29

For high-risk patients combination regimens of androgen deprivation therapy, EBRT and brachytherapy had higher progression-free survival than surgery, EBRT or brachytherapy alone. HDR brachytherapy for prostate cancer: Extremely conformal technique Real-time image guided needle placement HDR brachytherapy planning algoritms allow for doubledose optimization as it modulates the dwell times as well the dwell positions The overall treatment time reduction with HDR eliminates the uncertainties related to prostate volume changes that occur during the weeks following procedure (typical with LDR) Minimizes the problems of organ movement and patient positioning (typical with EBRT) HDR brachytherapy for prostate cancer: From radiobiology perspective, HDR may be favored as treatment delivery over period of minutes, instead of weeks or months, does not allow malignant cells to repopulate, advance through the cell cycle or recover from sublethal damage. As prostate cancer alpha/beta ratio is low, HDR biological effectivenes is higher than the LDR or EBRT From radiation safety perspective, HDR is better, because patients are not radioactive when they return home DARIUS NORKUS, KONSTANTINAS POVILAS VALUCKAS Institute of Oncology, Vilnius University External-beam radiotherapy (EBRT) has a long history of clinical use in the treatment of prostate cancer. Despite the perfect surgical treatment results from several experienced high volume centers, radiotherapy remains the treatments of choice for most high risk prostate adenocarcinomas. There 30 Most of reports from prostate cancer hypofractionated EBRT studies have focused on physician-rated toxicities. Only few have used validated patient-reported quality of life (QOL) questionnaires. Moreover, in most QOL studies data were not collected during the acute period of treatment, focusing only on change in late effects. We found QOL outcomes important because they could not correlate well with physician-related toxicities. In this report we describe both, physicianrelated early toxicities and patient-reported QOL measurements by validated Expanded Prostate Cancer Index Composite (EPIC), from the prospective randomized trial comparing hypofractionated and conventionally fractionated EBRT combined with androgen deprivation therapy for high risk prostate cancer patients. A single HDR radioactive source may deliver treatment to large numbers of patients DEVELOPMENT OF MRI DIAGNOSIS IN CERVIX CANCER HYPOFRACTIONATED RADIOTHERAPY FOR LOCALIZED PROSTATE CANCER: IOVU EXPERIENCE AND ONGOING TRIALS DARIUS NORKUS impact patient s lifestyle and possibly lowers biological benefit. Hypofractionation in the treatment of prostate cancer offers a shorter treatment course and increased convenience for patients. The data from hypofractionation studies indicate that the α/β ratio for prostate cancer is not very different from the α/β ratio for late-responding tissues of the bladder and rectum. If the prostate α/β value is significantly less than the α/β for late complications, significant increases in tumor control can be expected by changing from conventional fractionation to 20 or fewer larger fractions, without increasing the risk of early and late toxicity. The results to date support the conclusion that hypofractionated radiation therapy is relatively safe for the treatment of localized prostate cancer. No significant increase has been seen in the acute toxicity or the late adverse events. RŪTA GRIGIENĖ Institute of Oncology, Vilnius University KONSTANTINAS POVILAS VALUCKAS is a clear demonstration from conventionally fractionated radiotherapy dose escalation clinical trials of improved biochemical relapse-free survival rates with higher irradiation doses. Conventionally fractionated dose escalation, however, results in treatment protraction, which could negatively Cervical cancer is the fourth most common cancer among women in Lithuania and the most common cancer in young woman, under 35 years old. In 2010 there were 462 new cases of cervical cancer diagnosed. The morbidity for this disease in Lithuania is one of the highest in Europe. The screening for cervical cancer is performed in Lithuania from 2004. During 2004-2010 almost 730 000 women between 25-60 years were screened. Women between 2560 years have are screened once in 3 years for cervical cancer passing PAP test. Rūta Grigienė The treatment strategy is chosen according stage. FIGO classification is used to determine the stage. The diagnosis cannot be changed even the disease comes back or during surgery large spread was found. The main aim is clinical investigation. Stage is determined due to disease spread to surrounding organs: parameters, vagina, bladder, rectum. One of the main radiological tolls is MRI. Investigation is done in axial, coronary and sagittal cervix uteri plains. Tumor of cervix uteri T2 is seen as hyperintensive signal in comparison of low signal 31

normal cervix stroma. Evaluating tumor size and possible extend to vagina. In T1 regiment cervix uteri tumor almost the same as surrounding tissue. Intravenous contrast is not necessary for local spread evaluation. Diagnosis of parametrial invasion with MRI reaches 87-94%. The main criteria that there is no parameter infiltration-fibrotic ring around the cervix is seen in T2 MRI views. If such ring doesn t exist-it s the sign of parameter infiltration. MRI is the best imaging tool for local cervical cancer staging. MR imaging technique T1WI: axial, large field of view including entire pelvis T2WI: axial, sagital and coronal small field of view T1 C+: dynamic; optional, used not for staging but for demonstrating adjacent organ invasion or fistulas MR imaging Cervix carcinoma Axial T2WI through the cervix in a patient with endocervical carcinoma. An irregular infiltrative mass is evident, with a lobulated lateral margin consistent with paracervical extension. MR imaging T2 WI sagitttal view Axial T2 WI MR shows high signal intensity mass in the cervix. The low signal intensity stromas ring is seen. shows the high signal intensity mass in the cervix. The disruption of the stromal ring is seen IS IT REASONABLE TO USE SURGICAL TREATMENT FOR LOCALLY ADVANCED CERVICAL CANCER? VILIUS RUDAITIS VILIUS RUDAITIS Faculty of Medicine, Vilnius University The locally advanced cervical cancer or IB2, IIA1, IIA2, IIB stage cervical cancer is still a controversial issue in terms of how it 32 should be treated. Should radiotherapy be used alone or should it be combined with chemotherapy. According to the French cooperative group the 5-year survival rate was around 86 %, 80 %, 70 % for stages IB2, IIA, IIB treated only with radiotherapy using Fletcher s guidelines. Patients in Radiation Therapy Oncology Group trial 90-91 and 2 GOG trials who were treated with chemo radiation did even better. So, is there any space for us to improve survival rates by adding any novel medications or biological agents or maybe surgery? Probably no, but small trials are carried out around the world adding neoadjuvant chemo or neoadjuvant intra-arterial chemotherapy to downstage the bulky or already locally spread cervical tumors. The results are controversial because the majority of these patients would need the postoperative radiotherapy. Basically, we should follow a simple rule. In case the patient will need postoperative radiotherapy after the surgery (deep tumor infiltration, V/L invasion in the conisation specimen, close surgical margin, parametral infiltration, mts in the pelvic lymph nodes), she should be sent straight to the radiotherapy. Nevertheless, some patients with locally advanced cervical cancer are treated primarily with surgery. Surgery for the locally advanced cervical cancer is justified in cases of heavy bleeding from the primary tumor as well as in cases of young patients when surgical staging would help to find out if any lymph nodes are involved. Besides, transposition of the ovaries would definitely improve the quality of life. Patients with recurrent locally advanced post irradiated cervical cancer form another group that would benefit from surgery. In these cases exenterative radical surgery is the only and the last option to survive cancer, giving a 50 % survival probability. We made a retrospective analysis of the patients with cervical cancer who have been surgically treated in our institution during the last 4 years. 76 patients who underwent surgical treatment were included in this trial. 10 patients had locally advanced cervical cancer. The examination of postoperative specimen showed that 8 patients had pt2b and 2 patients had pt2a2 cervical cancer. 100 % of those patients received postoperative chemo radiation. The consequences, complications, rates of progression free survival of such treatment will be analyzed in the presentation. THE OPTIMISATION OF CERVICAL CANCER BRACHYTHERAPY ARTŪRAS INČIŪRA Lithuanian University of Health sciences Cervix cancer treatment was one of the major challenges for RT during first half of last century: treatment techniques and schedules were influenced by large scales centers or scools - Paris, Manchester, Stockholm. New technical possibilities during second half of last century: new sources and activities, afterloading technique, ARTŪRAS INČIŪRA treatment planing procedures imaging, computerized calculation. Metaanalysis of 19 concomitant chemoradiation trials showed 16% absolute improvement in PFS (47% to 63%) and 12% absolute improvement in survival (40% to 52%). Brachytherapy imaging and planning: X-ray (invisible tumour, uterus and OAR, dose prescription 33

to points A, dose to OAR points), CT (visible uterus and OAR, but invisible tumour, dose prescription to points A, dose to OAR DVH), MRI (all structures are visible, dose prescription to points A, optimisation to tumour, dose to OAR DVH). Groupe Europeen de Curietherapie/European Society for Therapeutic Radiology and Oncology (GEC/ESTRO) working group for gynecologic brachytherapy has been working on recommendation for recording and reporting three-dimensional (3D) image based BT for cervical cancer: dose-volume parameters for GTV, CTV, treated volume, OAR. GTV cervical tumour only. HR CTV (high risk) GTV + whole cervix + macroscopic tumour load. IR CTV (intermediate risk) GTV + macroscopic + microscopic tumour spread. Changes of tumour (GTV and CTV) during treatment (GTVB1, GTVB2, GTVB3). Evaluation of GTV and CTV: gynecological visualisation, palpation and MRI, GTVD (gross tumour volume at diagnosis), GTVBT (GTVB1, GTVB2, GTVB3 at brachytherapy). HR CTV for BT (HR CTVB1, HR CTVB2, HR CTVB3): GTV + whole cevix + extracervical tumour extension (palpation and MRI). Limited disease GTVB = GTVD. Advanced disease - whole cevix + extracervical tumour extension (palpation and MRI). Pathologic residual tissues (palpable indurations and/ or residual grey zones in parametria, uterine corpus, vagina or rectum and bladder on MRI are included in HR CTVB. A total radiation dose is prescribed to HR CTV appropriate to eradicate macroscopic disease. IR CTV for BT (IR CTVB1, IR CTVB2, IR CTVB3) significant microscopic tumour load, encompasses HR CTV with a safety margins of 15 mm (amount of safety margins is chosing according tumour size and location, potential tumour spread, tumour regression and treatment strategy). In limited disease (<4 cm) IR CTV: HR CTV - BTV + cervix + different safety margins, antero-posterior 5 mm (limited by rectum and bladder), cranial (to corpus uteri) and caudal (to vagina) 10 mm, lateral (to both parametria) 10 mm, in case of endocervical or lateral tumour growth additional 5 mm margin to direction of potential spread. In more extensive disease (>4 cm) IR CTVB: macroscopic tumour extension at diagnosis (GTVD) which is superimposed on the anatomical area at time of BT + different safety margins depending on the extent of the disease and regression at time of BT. Complete remission HR CTV + initial macroscopic tumour extension superimposed on topography at the time of BT without any safety margins. Good remission HR CTV and initial tumour extension at diagnosis. Poor remission (less than 10 mm) - HR CTV + 10 mm safety margin into direction of potential spread. Stable disease - initial macroscopic tumour extension superimposed on tomography at the time of BT + 10 mm safety margin. Paradigm shift from 2D point dose dosimetry to IGBT in HDR cervical cancer treatment needs advanced concept of evaluation in dosimetry with clinical outcome data about whether this approach improves local control and/or decreases toxicities. Long-term results of Cf-252 gamma neutron brachytherapy in treatment of Ca cervix uteri (IIB and IIIB) ERNESTAS JANULIONIS K.P. Valuckas, E. Janulionis, V. Atkočius Institute of Oncology, Vilnius University INTRODUCTION First data about Cf-252 brachytherapy were published by Y.Maruyama in 1976. HDR Cf-252 brachytherapy device was installed in Vilnius in 1990. Patients with carcinoma of cervix, corporis uteri, rectum, oesophagi and glioblastoma were treated. The questions to be answered about Cf252 were: carconogenetic action of the neutron source, RBE of Cf-252 and clinical efficacy of the HDR Cf-252 brachytherapy. Materials and methods The present study shows long term results regarding combined radiotherapy (EBRT+Cf-252 or Co-60 brachytherapy during 1990-1999 for 520 pts with Ca cervicis uteri (IIB and IIIB). No chemotherapy was used. The dose calculation was done using Rjabukin formula. There were 222 pts with IIB (135 of them with Cf-252 and 87 with Co-60) and 298 pts with IIIB (198 pts with Cf-252 and 100 pts with Co-60). There were no randomization. KONSTANTINAS POVILAS VALUCKAS Results 5 yr survival rate in IIB was equal in both groups: 54,2 % (Cf-252) versus 56,8 % (Co-60), as well as for IIIB stage: 43,7 % (Cf-252) versus 46,0 % (Co-60). Recurrence rate was lower in Cf-252 group: 9 VYDMANTAS ATKOČIUS % versus 15 %. What we were looking very carefully second malignances we found equally in both groups: 4,8 %. CONCLUSIONS It was concluded that Rjabukin formula worked well in reality. The overall survival rate was the same for each year of treatment as well for Cf-252 and Co-60 groups. The statistically significant difference was found for late complications (1990 1996 versus 1997 1999). Second primary rate was the same for Cf-252 and Co-60 groups. PATIENTS CHARACTERISTICS IIB 34 IIIB Cf-252 Co-60 Cf-252 Co-60 N 135 87 198 100 Age, yr. (median) 54,3 53,5 52,1 50,7 Follow-up, mos (median) 72,5 92,8 46,5 48,2 35

IIB IIIB Cf-252 Co-60 Cf-252 Co-60 78,5 77,0 74,2 81,0 Histopathology, %: SCC 6,7 4,6 9,6 7,0 Hemoglobin level, g/l (median) AdenoCa 121,0 119,0 120,0 119,0 Progressive local, % (median) 85,9 72,4 90,0 82,0 Brachytherapy in Poland J. Lyczek (Brzozow, Poland) J. Lyczek SURVIVAL IIB IIB, % n 5-y 10-y 15-y Cf-252 (1989-1999) 135 54.15 41.09 22.18 Co-60 (1989-1999) 87 56.84 49.42 30.84 Cf-252 (1997) 34 55.88 47.06 25.74 SURVIVAL IIIB IIIB, % n 5-y 10-y 15-y Cf-252 (1989-1999) 198 43.66 34.39 20.70 Co-60 (1989-1999) 100 46.00 37.82 15.44 72 51.39 41.54 28.45 Cf-252 (1997) SECOND PRIMARIES 36 37

THE HDR MULTiSOURCE SYSTEM FROM BEBIG AN INNOVATION WITH LARGE CLINICAL EXPERIENCE P. TONHAUSER (Berlin, Germany) The presentation described the requirements and possibilities which can expected today from a modern HDR brachytherapy system. As an example the Multisource afterloader was given. The implementation of additional QA tools like automatice source drive calibration systems, color markings for applicators and accessories (avoiding connection mismatches) and a 38 P. TONHAUSER fully integrated in-vivo dosimetry system ensure the accurate set-up of the system and an efficient control of doses at organs of risk, avoiding the need of additional devices. The integration of a miniaturized Cobalt-60 HDR source allows for less source replacements, bringing next to enourmes cost savings a reduced workload for the clinical technical staff plus less system downtime. 39

A modern HDR treatment planning system was introduced using the example of Eckert & Ziegler Bebig s treatment software HDRPlus. Integrated applicator dimensions and application libraries are reducing the treatment planning time drastically. 3-D reconstruction modes allow fast representations and reconstructions of virtually all modern imaging techniques (X-Ray, CT, MR, PET, Image Fusion). Data transfer to external IT-systems like hospital information systems or Record and Verification systems is possible via standardized DICOM and DICOM RT interfaces. Finally the biologically effective doses including summation with external radiation can be calculated In such a system. Keywords: Safety, Speed, Accuracy Economics and Connectivity MICROSATELLITE INSTABILITY IN ENDOMETRIAL CANCER AND CERVICAL PATHOLOGY DAIVA KANOPIENĖ DAIVA KANOPIENĖ Institute of Oncology, Vilnius University Background Microsatellite instability is the disorder in the sequences of microsatellites, formed by one or more recurring insertions or deletions of nucleotide bases. They occur randomly through the genome and are not eliminated from noncoding long or short microsatellites in the DNA that is an early event in carcinogenesis. Molecular mechanism responsible for mutations in microsatellite locations is a malfunction of a post replication DNA repair mechanism. In order to assess microsatellite instability various markers are used. National cancer institute of USA recommends examining five areas of genome using a set of five markers: D2S123, D5S346, D17S250, BAT25 and BAT26. While examining the microsatellite instability, more markers may be used. In addition, more accurate mononucleotide markers are constantly being designed. Original study identified the association of microsatellite instability with hereditary 40 colorectal cancer. Later microsatellite instability was identified in other cancer cases. Data on microsatellite instability of different cancers is still being collected. Objective Assess the frequency of microsatellite instability in endometrial cancer and cervical pathology. Study design: 309 women have been involved in the research study: 109 with endometrial cancer, 88 with cervical cancer and 112 with dysplasia cervicis uteri. Using a set of five mononucleotide markers: BAT25, BAT-26, NR-21, NR-24 and MONO-27, microsatellite frequency is being assessed. Results: After examining 109 women with endometrial cancer, 34 (31%) cases of microsatellite instability has been diagnosed. Frequency of microsatellite instability in endometrioid adenocarcinoma and nonendometrioid carcinoma has been compared 34% and 0% respectively. Also, cor- relation between microsatellite instability and tumor grade (24% for G1 and 76% for G2 - G3) and microsatellite instability and stages of disease (82% for stage I and 18% for stages III IV) has been discovered. In addition, examination (using these markers: BAT-25, BAT-26, NR-21, NR-24 and MONO27) of 200 women with cervical pathology, did not reveal the microsatellite instability. Conclusion Microsatellite instability in endometrial cancer has been detected in 31% of the cases. Microsatellite instability is a potential marker of poor prognosis of endometrioid adenocarcinoma. Microsatellite instability in cervical cancer and dysplasia cervicis uteri has not been detected therefore different microsatellite markers should be evaluated. BRACHYTHERAPY IN PENILE CARCINOMA A.P.GERBAULET-LE GAONACH (Paris, France) GENERALITIES Incidence: Penis ca is rare 1-2% of male ca in Europe, but rate is higher in China, Africa or Brazil 10-15%. Pathology: 90% of SCC, 15 to 50% of preinvasive lesions. Role of HPV, hygien, smegma and phimosis+++. Desease extension: local (MRI), balanoprepepucial sulcus, shaft, urethra; regional groin nodes (US, more recently dynamic scintigraphy for the identification of a sentinel node ); metastasis. TREATMENT MODALITIES Surgery: primary tumour: from Mohs micrographic surgery to total amputation; nodes: groin nodes lymphanenectomy (sentinel node), in selected cases lymphadenectomy can be extended to pelvic and paraaortic nodes. Large circumcision constitues an essential first step of all treatments. External beam irradiation: primary tumour: special device (plastic box), tissue equivalent material, parallel opposite fields, A.P.GERBAULETLE GAONACH but difficulties for reproductiblity; classical dose 60 to 70Gy. Nodes: prophylactic 4550 Gy, of necessity 65-75Gy. Brachytherapy: Two kinds: interstitial, contact, different dose rates (LDR+++, MDR, HDR+,PDR) 1) Interstitial brachytherapy Classical method (PierquinChassagne):After healing of the previous circumcision, insertion of a Foley catheter, evaluation of the GTV, implant of hypodermic needles, equally distant and parallel, maintened by two opposite handmade templates fixed by plaster trips. A perforated sponge, according to the penis size, sliding over the penis yo immobilize it and to push away the radioactive sources. Finally manual loading is performed with iridium wires with length adapted to the treated volume. Modern method : ( GAG Glans Applicator of Gerbaulet): This system allows a strict parallelism during all the irradiation, decreases pain and risk of infection and also 41

to establish in advance the volume necessary to be implanted. This device consists of 2 transparent plastic plates, perforated each 5 mm, with 4 threaded screws inserted at each angle of the plates. The same system of hypodermic needles, sponge and iridium loading is used as the classical methods. In the 2 LDR methods and for PDR Paris system rules must be respected. A total dose is 60-70 Gy delivered in 4-6 days In case of use of remote afterloading projector the needles are replce by plastic tube, and iridium wires by miniaturized stepping source. One exemple of HDR (plesiobrachytherapy) 2) Plesiobrachytherapy Is indicated for well limited and superficial lesions. 2 devices can be used, more often plastic cylinders, or mould applicator made in order for each patient. For HDR different schedules were proposed: for exemple 30Gy/12fr/30 days with a boost of 15Gy/5fr/11 days one month later (Horiot). Other more recent recommendations are also presented. INDICATIONS: Brachytherapy alone is the gold standard for tumours up to 4 cm, limited to the glans. Surgery is indicated as salvage treatment or more specifically for tumours >4-5 cm, exceeding beyong the glans. In these large tumours if patient refuses surgery combination external beam irradiation brachytherapy is proposed. In case of contra-indications of these treatments external beam irradiation alone is used. RESULTS: 1) Surgery The largest series or surveys shown a 5-year survival rate of 42-54%. A coopera- 42 tive study led by the French National Federation of Cancer Centers has included 506 pts, the 5-year cancer specific survival and the local control were respectively 75 and 84% 2) External beam irradiation In Different publications the results are comparable, the survival rate is between 51 to 65% but by definition the penis preservation is obtained in more cases. Partial breast irradiation B. McCormick (New York, MSKCC, USA) B. McCormick 3) Brachytherapy In one table in which are only presented series including more than 50 patients. LDR interstitial is the main treatment, 80% of patients presented at the time of diagnosis T1T2 (stage I in Jackson classification). The 5-year overall survival rate is 70-75%, the local control 80 to 85 %, the penis was conserved in 75% of patients; the complications are not very often detailed around 25% of cases. A survey including 259 patients divided into 2 groups (Brachytherapy alone 184 pts, brachytherapy + external beam irradiation or surgery 76 pts shown better results for the first group particularly for the penis preservation: 76% vs 64%. In our own institution from 1970 to 2003 156 pts were treated by interstitial LDR brachytherapy. 28% of pts had a ca associated wiyh phimosis, 27% with precancerous lesions. Local recurrence: 18%, penis conservation 73%, nodes relapse 7%. CONCLUSION If brachytherapy is an effective treatment patients must well selected, tumour confined to the glans and the technique used perfectly adapted. Simple and safety afterloading system can be employed allowing a good tolerance for the patient, a control of dose distribution. 43

RADIATION INDUCED HEART MORBIDITY AFTER ADJUVANT RADIOTHERAPY FOR LEFT BREAST CANCER AISTA PLIESKIENĖ Klaipeda University Hospital Radiation therapy remains an important modality in the multidisciplinary treatment of breast cancer. Radiation significantly reduces the risk of local and regional recurrence after breast-conserving surgery and imparts a long-term survival benefit. Radiation-associated heart disease has been correlated with dose and increasing volume of irradiation. Late effects of radiation to the heart after adjuvant radiotherapy for left breast cancer include ischemic heart disease, valvular disease, conduction abnormalities, or heart failure. Irradiation to the left breast is not associated with a higher risk of cardiac death up to 20 years after treatment, but is associated with an increased rate of diagnoses of coronary artery disease and myocardial infarction compared with right breast treatment. Individual cardiovascular risk increases with personal or familial history of cardiac disease, age, smoking, hypertension, abnormality in the lipid profile, diabetes. Statistically significant correlation was found between hyper- 44 AISTA PLIESKIENĖ tension and left-sided breast irradiation in development of coronary artery disease. Current concepts of three-dimensional, computed tomography-based treatment planning, routinely use of set-up verifications allows individualized planning adapted to individual anatomy, can provide fieldshaping capabilities to minimizing critical normal tissue exposure and optimizing the delivery of radiation therapy. The data from clinical trial emphasize the need for further refinements in the radiation techniques for treatment of left-sided breast cancers that consistently reduce the volume of irradiated heart to minimize the risk of late toxicities in this patient population with a substantial opportunity for long-term survival. Modern radiotherapy modalities like tomotherapy and multifield intensity-modulated radiotherapy planning, gating techniques reduce cardiac doses in left-sided breast cancer patients with unfavorable cardiac anatomy. Heart Dose Constraints (conventional fractionation) 45

Deep inspiration breath hold treatment based technique O. Utehina (Ryga, Latvia) 46 47

TREATMENT OF HEAD AND NECK TUMORS RELAPSES WITH HDR BRACHYTHERAPY VIKTORAS RUDŽIANSKAS VIKTORAS RUDŽIANSKAS Lithuanian University of Health Sciences The aim of this study was to evaluate the results of hypofractionated accelerated CTguided interstitial HDR-BRT using 2.5 Gy per fraction. From December 2008 to March 2010, 30 patients were treated for the recurrennce of previously irradiated head and neck cancer. Thirteen patients underwent surgical resection followed by HDR-BRT to the tumour bed. Seventeen patients were treated with HDR-BRT only. All patients received 2.5 Gy twice per day to a total dosage of 30 Gy. The overall survival rate (OS) for the entire group at 1 and 2-years was 63% and 47% respectively; local control (LC), 73% and 67%; and disease-free survival (DFS) was 60% and 53%, again respectively. Patients treated with surgical resection and HDR-BRT showed an improvement in 2-year LC (77% vs. 47%, p = 0.013) and 2-year OS (62% vs. 35%, p = 0.035) compared to the patients treated with HDR-BRT only. Median overall survival for pre-treatment tumour volumes 36 cm3 was 22 months against 9,2 months for > 36 cm3 (p = 0.038). Grade III and IV late complications occurred in 3% of patients. No Grade V complications occurred. The Interstitial HDR brachytherapy regimen using 2.5 Gy twice daily fractions to a total dose of 30 Gy has been shown to offer an effective treatment option for patients with recurrent previously irradiated head and neck cancer with a low rate of late high grade toxicity. Surgical resection had a positive effect on the survival and local control in the management of patients with recurrent head and neck cancer. therapy, radiation, and surgical excision. These treatments wreak considerable havoc upon non-cancerous tissue and organs, resulting in harmful and sometimes fatal side effects for the patient. Therefore many new technologies are offered to bring new solutions for fighting this disease. One of them, introduced into clinical practice about twenty years ago, is photodynamic therapy (PDT), a minimally invasive therapeutic modality presently approved for treatment of several types of cancer and non-oncological disorders. Though PDT is a selective modality, it can be further enhanced by combining other targeted therapeutic strategies that include the use of nanoparticles for selective delivery of photodrugs. Based on the recent progress in nanobiotechnology, nanoparticles have the potential to become useful tools as therapeutic and diagnostic tools in the near future. Nanotechnology is, in part, a science of synthesizing molecular sized materials that can range from a few nanometers to micrometers that are invisible to the human eye. At this nanoscale, the tensile strength, optoelectrical properties, and surface chemistry of materials become radically changed. Due to nano-dimensions, unique optical properties, high stability and easy surface modification by binding different functional groups and Why a nanoparticles? biomolecules, semiconductor quantum dots and other nanoparticles are considered as promising materials for many biological and medical applications for fighting cancer. The ability to incorporate drugs into nanosystems displays a new paradigm in pharmacotherapy that could be used for celltargeted drug delivery. The drugs can be coupled to nanocarriers that are specific for cells and/or organs. Thus, drugs that are either trapped within the carriers or deposited in subsurface oil layers could be specifically delivered to organs, tumors and cells. These strategies can be used to concentrate drugs in selected target tissues thus minimizing systemic side effects and toxicity In addition to these therapeutic options, nanoparticle-based molecular imaging displays a field in which this new technology has set the stage for an evolutionary leap in diagnostic imaging. Cancer specific nanoparticles provide a new tool to enable non-invasive visualization of diseasespecific molecular and tissue changes with subcellular spatial resolution. Nanotechnology has advanced greatly in recent years and can be applied to variety of biomedical research areas, as well as optical biopsy in clinical settings in cancer treatment. Why a nanoparticles? The 1-100 nm scale is of interest for biological interfaces; for example, objects less than 12 nm in diameter may cross blood-brain barrier (Oberdorster et al. 2004; Sarin et al. 2008; Sonavane et al. 2008), POSSIBLE APPLICATIONS OF NANOTECHNOLOGIES IN CANCER THERAPY RIČARDAS ROTOMSKIS Modern Radiation Oncology Palanga 2012. 09. 15, Ricardas Rotomskis 7 A particle generally ranging in size from 1 nm to 100 nm. Nanoparticles are generally used as carriers for therapeutic or diagnostic agents. Can be solid or hollow. Composed of lipids, gold shells, dendrimers, semiconductors, metals and etc. Modern Radiation Oncology Palanga 2012. 09. 15, Ricardas Rotomskis 8 RIČARDAS ROTOMSKIS Institute of Oncology, Vilnius University Cancer is a leading cause of death worldwide. Late diagnosis and inefficient treatment lead to large number of deaths every year. 48 and objects of 100 nm or less can be endocytosed by cells (Conner and Schmid 2003). Current first-line treatments for most cancers feature a short-list of highly potent and often target-blind interventions, including chemo49

Principles of the photosensitized tumour therapy Principles of the photosensitized tumour therapy Application of PTT Injection of the photodrug (photosensitizer) into an organism and its transport (0-3 h). Distribution of the photodrug in tissues. MOLECULAR BIOMARKERS FOR THE INDIVIDUALIZED RADIOTHERAPY: MYTH OR REALITY Different accumulation of the photodrug in cancerous and normal tissues (after 24-72 h). Photoexcitation of the photodrug. Initiation of photochemical reactions. Damage of biomolecules. Impairment of intracellular biochemical reactions. Structural damage of cells. Tumour necrosis. Modern Radiation Oncology Palanga 2012. 09. 15, Ricardas Rotomskis 19 Modern Radiation Oncology Palanga 2012. 09. 15, Ricardas Rotomskis APPLICATION OF MAGNETIC NANOPARTICLES IN CANCER IMAGING AND THERAPY Vytautas Kulvietis VYTAUTAS KULVIETIS, VITALIJUS KARABANOVAS, ARŪNAS JAGMINAS, RIČARDAS ROTOMSKIS Institute of Oncology, Vilnius University Faculty of Physics, Vilnius University State Research Institute Center for Physical Sciences and Technology Early detection and treatment of cancer is the most important component of a favorable prognosis. Over the past decade, concepts and tools derived from nanotechnology have been applied to overcome the problems of conventional techniques for advanced diagnosis and therapy of cancer. Recently, magnetic nanoparticles (MNP) were applied in the MRI as efficient contrast agents. These NP can be synthesized with favorable size and surface properties for optimal performance, e.g. they can be functionalized with specific biomarkers for cellular recognition in the organism and selective tumor imaging. MNP were shown as efficient agents for the lymph node imaging and for the assessment of the tumor infiltration in the nodes. Additionally, MNP might be modified with fluorescent molecules in order to combine MRI with non-invasive optical imaging which, later on, is used for intraoperative tumor imaging. Due to the paramagnetic properties MNP vibrate and heat up in the presence of alternating magnetic field and this effect is used to induce hyperther50 KĘSTUTIS SUŽIEDĖLIS Institute of Oncology, Vilnius University 20 mal tumor destruction. Recently MNP were approved for glioblastoma thermotherapy and the method is under clinical trials for prostate and pancreatic carcinomas. More to add, MNP are developed for the controlled release of cancer drugs through the application of an external magnetic field. These modalities enable to use MNP simultaneous for tumor imaging and therapy and implement the concept of theranostics. However, despite of the potential benefits of the MNP in the biomedical applications, there are some questions which have to be answered for optimal MNP performance and minimal side effects. The main problems include: chemical stability and biocompatibility of the MNP, surface functionalization for selective interaction with biomolecules, favorable in vivo distribution, proper clearance pharmacokinetics, absence of undesirable biological effects and other. Therefore the Institute of Oncology of Vilnius University started the research on MNP biodistribution and biological effects using in vivo and in vitro model system KĘSTUTIS SUŽIEDĖLIS Radiotherapy is one of the most common and effective therapies for cancer. Approximately 50% of all cancer patients will receive radiotherapy at some point during the treatment for their disease. However, tumor radioresistance, including intrinsic and acquired radioresistance during the therapy, may account for some treatment failures and recurrence of disease. Comprehensive mechanisms of the changes in radiosensitivity of cancer cells as well as acquired radioresistance remain unclear, nevertheless molecular biomarkers to predict tumor radiosensitivity are on demand and the research aiming to establish these molecular biomarkers to individualize radiotherapy is performed. Problem is viewed prom the point of current knowledge in molecular cancer biology using data of research performed world wide as well as at Institute of Oncology Vilnius University. Tumours are complex structures Molecular biology of cancer Adapted from D. Hanahan and R. Weinberg. Cell. 2011 Which change during? the radiotreatment Irradiation of MCF7 cell line culture in vitro Conclusion Ionizing radiation induces efficient mechanism of repair of double strand DNA breaks; IR of cancer cells resistant to irradiation arrests cell cycle in G2 phase; MCF7 cells not irradiated MCF7 cells which survived the irradiation of the dose of 44 Gy (2 Gy x 22) Molecular biomarkers for the individualization of radiotreatment is the REALITY: expression of genes involved in homologous recombination, activity of CDK1 are potential biomarkers (but clinical significance has to be validated); 51

treatment procedure and therefore ensure the quality of the treatment that the correct dose will be administered to the patient. EVALUATION OF EXPOSURE DOSES IN HEAD AND NECK BRACHYTHERAPY Diana Adlienė DIANA ADLIENĖ, JURGITA LAURIKAITIENĖ Lithuanian University of Health Sciences The main objective of modern radiotherapy techniques is to ensure an accurate and safe dose delivery to the patient, avoiding unnecessary irradiation of the healthy tissues. In this frame special attention should be paid to the head and neck cancer (HNC) patients due to the anatomical aspects of this region: close proximity of critical organs (spinal cord, brain stem, temporal lobes, and salivary glands). Head and neck patients mostly are treated using external photon beam irradiation. However, as an alternative, the treatment can also be performed using radioactive sources placed within the tumour, afterloading brachytherapy [1-2]. The accuracy in brachytherapy depends on several physical parameters, such as source activity, source position, irradiation time, implant reconstruction, and dose calculation algorithm of the treatment planning system (TPS). Therefore, the main issue of the treatment verification is to check planned dose prior starting the treatment, verify the delivered dose during the treatment and verify treatment completion after treatment procedure [3]. Verification of used technological methods or techniques either in external beam radiotherapy (EBRT) or even in brachytherapy (BRT) is a challenge for medical physicist, especially choosing the most appropriate method for dose measurement. Ion chambers, thermo-luminescence detectors (TLDs), semiconductor devices and X-ray films are commonly used for relative dose measurements, however only in very few 52 Acknowledgement This work was partially funded by a grant No.MIP-082/2011 Clinical and physical aspects in the head and neck cancer brachytherapy from the Research Council of Lithuania. Jurgita Laurikaitienė cases these measurements are performed in vivo. Another limitation of introduced dosimetry methods is 1D or 2D geometry. Today 3D dose verification technique such as gel dosimetry is suggested to verify the outcome of the planned dose to the target with a treatment planning system however it needs accurate dose calibration. Verification of the treatment accuracy using different dosimetry methods, comparison of calculated and delivered dose (as measured in vivo) and determination of possible deviations was the main aim of this study. More precise delivery of radiation to the tumour enables sparing of the healthy tissues; this is a key point to make attempts to control the dose escalation under special circumstances. Planning the treatment in HDR brachytherapy, dose distribution has to be known with a good precision and accuracy [4]. Patient dose in vivo measurements in situ have been performed during cancer treatment procedures in head and neck brachytherapy. Experimental results were comparable to those derived from calculations performed using a standard dose planning system, however some small deviations were identified. Additionally relative dose evaluation (in vitro) using special calibrated dosimeters were performed to assure quality of the brachytherapy treatment. Application of different dosimetric methods allow to enhance the understanding of the realistic clinical data and are of advantage detecting significant errors during the References: 1. Carrara M., Fallai C., Gambarini G.and et al. Fricke gel-layer dosimetry in high dose-rate brachytherapy. Applied Radiation and Isotopes, 68 (2010). p. 722 725. 2. Zuchora A., Kabacińska R., Terlikiewicz J. Evaluation of spinal cord risk during HDR brachytherapy in patients with nasopharyngeal cancer Reports of practical oncology and radiotherapy, 11 (2006). p. 9-12. 3. Kolkman-Deurloo I. K. K., de Kruijf Wilhelmus J.M., Levendag P. C. On-line implant reconstruction in HDR brachytherapy Radiotherapy and Oncology, 78 (2006). p. 53 59. 4. Gerardy I., Rodenas J., Dycke M., et al. Dosimetric characterization of a brachytherapy applicator using MCNP5 modelisation and in-phantom measurements. Applied Radiation and Isotopes, 68 (2010). p. 735 737. 53

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