JOURNAL TRANSCRIPT
Research Program Radiological Diagnostics and Therapy
Clinical Cooperation Unit Radiation Oncology
Clinical Cooperation Unit Radiation Oncology (E0500) Head: PD Dr. med. Dr. rer. nat. Jürgen Debus Scientific concept of the clinical co-operation unit radiation oncology
Scientists Dr. Christian Bohris (06/99 -12/99) Pierre Branitzki Isabell Braun Bernd Didinger Dr. Claudia Frank (-01/99) Dr. Martin Fuß Dr. Peter Heeg (-10/99) Dr. Karin Henke-Wendt Dr. Klaus Herfarth Peter Hipp Dr. Jürgen Jenne * Dr. Frank Lohr Dr. Marc Münter Dr. Peter Peschke * Dr. Andrea Pirzkall Dr. Ralf Rastert Dr. Jens Rickert Dr. Daniela Schulz-Ertner Dr. Ioannis Simiantonakis Dr. Julia Spoo (-06/99) Dr. Anke Strunz Dr. Christoph Thilmann Dr. Gabriela Westphal (-05/99) Dr. Angelika Zabel * Dr. Ivan Zuna *
256
Guest scientists Dr. Tetsuya Yamada (4/98 - 03/99) Postgraduate students Silke Aumann Heike Corban-Wilhelm Michael Hlavac Jürgen Kreß (-05/99) Daniel Röder
Klaus Braun Stefan Haas Maria Kissel Peter Reinacker (-08/99) Alexandra Schlicker (-01/98)
Graduate students Matthias Moosmann (8/98-8/99) Horst Strohmeyer (10/98-10/99)
The aim is the development of new radiooncological strategies. Over the past two years substantial contributions to the radiooncological treatment of patients were made. This includes not only improved technological approaches to treatment delivery but also the development of biologically based optimisation of radiation effects. These tasks were performed in very closed co-operations with the department of medical physics Prof. Schlegel and the other departments of the research program. Due to a close co-operation with the department of radiation oncology at the university hospital of Heidelberg it was possible to conduct a clinical phase I, I/II and phase III trial. An essential task of the clinical co-operation unit will be the conduction of phase I/II and phase II trials which examine safety and reliability of reasontly established therapeutic methods an planning procedures. The optimisation of computerised radiotherapy planning and simulation may hereby provide substantial improvement of the results. Moreover it is our aim to examine if the individual radio sensitivity can be predicted by molecular biological approaches and also eventually therapeutically controlled. Carbon ion radiotherapy has an increased radiobiological effectivity and allows precise dose deposition. In the frame work for a collaborative study we are investigating the application of heavy ion therapy in patient system base of skull tumours. Moreover new approaches with non-invasive therapeutic methods for example the use of high intensive ultrasound therapy in the treatment of tumours is evaluated. The main goal of the clinical co-operation unit is to enhance translational research in the area of radiation oncology. Dose distribution for fractionated radiation therapy of an acoustic neuroma. A steep dose gradient to the adjacent brainstem is visible (further details arepresented on p. 258).
Technicians Gabriele Becker * Petra Brade * Dietmar Greulich * Renate Haselmann Stefan Hauser (1/99-) Sabine Kuhn Rainer Kühnlein * Miriam Lenz Anke Menges (-04/99) Annette Miltner Heike Reutner Tobias Richter * Annemarie Schrödersecker*Stephanie Stauch Alexandra Tietz * Cora Weyrich (-03/99) Civilian draftees Matthias Jäckel (-09/99) Phillip Klinkhard (-09/99) Danny Kappenstein (-10/99) Christian Bretthauer Marcus Thiemer * = funding of the DKFZ
DKFZ 2001: Research Report 1999/2000
Research Program Radiological Diagnostics and Therapy
Clinical Cooperation Unit Radiation Oncology Fig. 1: Dose distribution of IMRT treatment of a woman with breast cancer after breast conserving surgery. The target volume consists of the breast and the parasternal lymphatic tissue. Left side: IMRT with 12 intensity modulated beams. Right side: conventional treatment with 2 tangential wedged beams. Displayed isodoses: 10%, 20%, 30%, 50%, 90%, 95%, 105% ———, 110%
Conformal Radiotherapy Using Intensity Modulated Beams The goal in radiotherapy is to achieve local tumor control without exceeding tolerance doses of the surrounding radiosensitive normal tissue. New conformal techniques in radiotherapy try to adapt dose distribution as closely as possible to the target volume. This could be realised using multiple portals with individual beam shaping. However, there are cases of complex shaped tumors in close relationship to organs at risk where no sufficient dose distribution could be achieved with conventional technique. This could be seen especially in concave shaped targets enclosing organs at risk. An improvement in dose distribution could be achieved using divers intensities within each portal. Thus, dose escalation to the tumor without increased complication rate seems possible in several cases. In the past efforts were taken to develop utilities for radiotherapy planning, delivery and verification of intensity modulated beams. An inverse planning software (KonRad®) to calculate the required intensity profiles for the desired dose distribution was developed at the DKFZ. Different techniques are available for delivery of intensity modulated beams. The first clinical application was carried out with cerrobend compensators. The beam intensities are modified due to the 2-dimensional thickness profiles of the metal absorber. Most patients were treated with IMRT in ‘step-and-shoot’-technique. Here the intensity profiles are divided into multiple subsegments which are formed by a multileaf collimator. Due to steep dose gradients between target volume and organs at risk and the application of a set of small portals special attention is given to reproducibility of patient set up and verification of the calculated dose distribution. A stereotactically guided set up device was developed for head fixation and for whole body fixation as well. The final dose distribution calculated for patient treatment is verified in phantom measurements. Special phantoms were designed for verification of treatment plans for head and neck, abdomen and thorax. A quality assurance program was established to check the difference between applied and desired treatment plan and if necessary to correct the applied plan.
The clinical feasibility of IMRT is tested for different tumor sites in the phase II study ‘Conformal Radiotherapy with Intensity Modulation’ which is activated since 31.7.98. First patients included in the study were patients with complex shaped meningiomas of the skull base. Until now 45 patients were treated in cases in which a satisfying dose distribution was not achievable with conventional treatment techniques [4]. In all patients a treatment with beam intensity modulation was feasible. A mean dose of 55.8 - 58.2 Gy was applied in 5 - 7 coplanar beams in ‘step-andshoot’-technique with 5 intensity levels. Only 9 patients were treated with a higher number of beams or a noncoplanar beam configuration. In total 125 patients were treated with IMRT at the DKFZ with the following diseases: - base of skull tumors [1,4] - tumors of the head and neck [3] - paraspinal metastases and tumors [5, 9] - mesothelioma - prostate cancer [2] - breast cancer after breast conserving surgery [8] For these indications the use of IMRT is feasible and safe in the tumor sites mentioned above with the fixation devices available in our department. IMRT may prove to be a valuable therapeutic modality for complex shaped target volumes adjacent to critical structures. Here, a special focus is the improvement of radiotherapy of breast cancer, which is part of the HGF research project ‘Diagnosis and therapy of breast cancer’. The aim is implementation of IMRT into clinical routine of breast cancer. A promising example of a patient with left sided breast cancer is shown in figure 1. Because of medial tumor site, the parasternal lymph nodes were included into the target volume. In these cases improvement of local control and reduction of side effects can be expected. A phase II study is planned for this subgroup. Additionally, IMRT enables to introduce new principles into radiotherapy. An integrated boost as a new treatment concept. It delivers a high dose to the macroscopic tumor site and simultaneously a homogeneous dose to the surrounding tissue of microscopic spread. In a treatment planning study for malignant gliomas we could demonstrate the su-
DKFZ 2001: Research Report 1999/2000
257
Research Program Radiological Diagnostics and Therapy periority of an integrated boost based on inverse planned IMRT over forward planned SCRT [6,7]. To compare the effectiveness of this treatment procedure with conventional treatment of patients with high grade gliomas a phase III trial is initiated. Publications (* = external co-author) [1] Debus J., Pirzkall A., Thilmann C., Grosser K.H.,Rhein B., Haering P, Hoess A., *Wannenmacher M.: IMRT in the treatment of skull base tumors. Radiother Oncol 2000; 56 S1: 86. [2] Didinger B., Thilmann C., Zierhut D., Schlegel W., *Wannenmacher M., Debus J.: Vergleichende Untersuchungen zur Organbeweglichkeit und Volumendefinition mittels CTgestützter Positionierkontrollen während IMRT bei Patienten mit Prostatakarzinom. Strahlenther Onkol 2000;176: S1: 16. [3] Münter M., Thilmann C., Rudat V., Haering P, Rhein B., Schlegel W., *Wannenmacher M., Debus J.: Inverse Bestrahlungsplanung und intensitätsmodulierte Strahlentherapie (IMRT) fuer Tumoren des Kopf- und Halsbereiches. Strahlenther Onkol 2000;176: S1:18. [4] Pirzkall A., Carol M., Lohr F., Höss A., *Wannenmacher. M, Debus J.: Comparison of intensity-modulated radiotherapy with conventional conformal radiotherapy for complex-shaped tumors. Int J Radiat Oncol Phys Biol (2000) 48: 1371-1380 [5] Pirzkall A., Lohr F., Rhein B., Höss A., Schlegel W., *Wannenmacher M., Debus J.: Conformal radiotherapy of challenging paraspinal tumors using a multiple arc segment technique, Int J Radiat Oncol Phys Biol (2000) 48: 1197-1204 [6] Thilmann C., Zabel A., Grosser K.H., Debus J., *Wannenmacher M.: Intensitätsmodulierte Strahlenbehandlung (IMRT) mit einem integrierten Boostkonzept (IBC) zur Strahlenbehandlung maligner Gliome. Strahlenther Onkol 2000;176: S1:16.
258
[7] Thilmann C., A. Zabel, K. H. Grosser, A. Hoess, J. Debus: Intensity Modulated Radiotherapy (IMRT) with an Integrated Boost Concept for the Treatment of High Grade Gliomas. Radiology 217(Suppl.): 443 (P) [8] Thilmann C., Zabel A., Grosser K.H., Harms W., *Wannenmacher M., Debus J.: Intensitätsmodulierte Strahlenbehandlung (IMRT) einer Patientin mit bilateralem Mammacarcinom. Strahlenther Onkol 2000;176: S1:33. [9] Thilmann C., Herfarth K.K., Lohr F., *Wannenmacher M., Debus J.: Wertigkeit der stereotaktischen fraktionierten Rebestrahlung in der Palliativtherapie von Wirbelsäulenmetastasen. Strahlenther Onkol 2000;176: S1:70.
Clinical Cooperation Unit Radiation Oncology
Stereotactic Radiation Therapy of Cranial and Extracranial Targets In cooperation with: Div. of Radiation Physics (Prof. Dr. W. Schlegel); Div. of Oncological Diagnostic and Therapy (Prof. Dr. G. van Kaick ) DKFZ
Stereotactic radiation therapy has the potential of delivering a high radiation dose to a defined tumor volume with a steep dose gradient to the surrounding normal tissue. We have evaluated the use of stereotactic radiation in several tumor entities [1-8]. Some of the results are discussed more in detail:
1. Acoustic neuroma [3] Acoustic neuromas were traditionally treated by surgical resection. However, fractionated stereotactic radiation therapy might be an alternative to the traditional approach. We have treated 51 patients with acoustic neuromas using fractionated stereotactic radiation therapy since 1989. Ten patients suffered from genetic disease of neurofibromatosis type II. The mean target volume was 8.6 ccm (range 2.2 - 32.4 ccm). The median applied dose was 57.6 Gy with single doses of 1.8 Gy daily. With a mean follow-up of 42 months (max. 131 months), there was only one radiological recurrence. The actuarial tumor control was 100% after 2 years and 95% after 5 years. 46.5% of the tumors showed a marked volume reduction. A complete response was observed in 4% of the patients. Nearly all patients showed a central loss of contrast enhancement as a sign of treatment response. Long term side effects could be limited: The chance of remaining hearing function was 85% after 5 years. Patients without genetic disease have a 100% chance of normal hearing function after this time. In addition, only one patient with a neurofibrosis showed a dysfunction of the facial nerve. Two patients developed neuralgia of their trigeminal nerve. Our results are superior to published neuosurgical series and to radiation series using the gamma knife if tumor control and side effects are taken in to account. The results show that fractionated stereotactic radiation therapy might have a major role in the treatment of acoustic neuromas. (Fig.1)
2. Meningeomas of the skull base A complete surgical resection of meningeomas of the skull base is often not possible. This is due to the close neighborhood of major blood vessels and the optic nerves. Fractionated stereotactic radiation therapy might be the treatment of choice for patients with this kind of tumor. 180 patients with low-grade meningeoma of the skull base were treated at the dkfz between 1985 and 1998. Most of the cases were complex shaped large tumors (median volume: 52.5 ccm). The tumors were treated with a median total dose of 57.8 Gy with 1.8 Gy single doses. Each radiation portal was shaped using a mid-size multileaf collimator. The median follow-up was 35 months. Only three patients showed recurrent disease during follow up. The actuarial survival was 97% after 5 years and 96% after 10 Fig.1: Dose distribution for fractionated radiation therapy of an acoustic neuroma. A steep dose gradient to the adjacent brainstem is visible (figure in full colours is presented on p. 256).
DKFZ 2001: Research Report 1999/2000
Research Program Radiological Diagnostics and Therapy years. 14% of the patients showed a partial response, and neurological deficits improved in 44% of the patients. Neurological improvement was not correlated with tumor volume decrease. Radiation side effects could be limited to 3.3% (6 patients). Our data show the effectiveness of fractionated stereotactic radiation treatment of skull base meningeomas. Comparision of our results with other techniques underlines the potential of this treatment compared to neurosurgery with or without conventional radiotherapy.
3. Chordomas [2] A typical location for chordomas is the clivus in the skull base. Since these tumors are relatively radioresistant, high radiation doses have to be applied for sufficient tumor control. However, using conventional techniques, major side effects are likely due to the neighborhood of radiosensitive brainparts. Using proton or heavy ion radiation therapy, local tumor control rates of 60% can be achieved. However, these techniques are expensive and limited to certain regions in the world. We treated 37 patients with skull base chordomas using fractionated stereotactic radiation therapy between 1990 and 1997. The median total dose was 66.6 Gy using 1.8 Gy single fractions daily. The median target volume was 56 ccm (17 - 215 ccm). With a median follow-up of 27 months, the actuarial 5 years tumor control rate was 50% with a probability of survival of 82%. Only one major side effect was observed: An 81-years old woman showed a brainstem infarction 25 months after therapy. However, she also showed areas of infarction in other parts of the brain. Using fractionated stereotactic radiation therapy, chordomas can safely be treated with only minor decrease in local tumor control compared to ion therapy. However, we hope to improve these results further using dose escalation with carbion ion therapy.
4. Liver tumors [5, 9, 10] Several more a less invasive local techniques are available for inoperable liver tumors. We have evaluated a non-
Clinical Cooperation Unit Radiation Oncology invasive technique for the treatment of these tumors using stereotactic single-dose radiation therapy. Between 1997 and 1999, 37 patients with a total of 60 liver tumors were treated using this method in a phase I/II trial. The dose was escalated from 14 Gy to 26 Gy at the isocenter. With a median follow-up of 6 months (1 - 26 months) there was an actuarial local tumor control of 80% after 18 months if the first 5 cases were excluded. This result could be achieved without any major side effects. Local failures were mainly due to low dose (low dose total or low dose at the tumor margins). Patient survival depended significantly on the presence of other extrahepatic systemic metastases at the time of treatment. Our results show that stereotactic single-dose radiation therapy is a feasible, effective and safe method for the treatment of inoperable liver tumors if the tumors are limited in size and not directly adjacent to bowel parts. (Abb.2)
5. Prostate cancer [4] Improvements in local tumor control of prostate cancer can be achieved if the applied radiation dose is escalated. However, dose escalation is limited if nearby radiosensitive organs like bladder or rectum cannot sufficiently spared from the high dose region. Intensity modulated therapy (IMRT) might be the answer for further dose escalation, if an accurate and reproducable positioning of the patient allows closer safety margins around the prostate. We have evaluated the self-developed body mask, which is normally used for the treatment of paraspinal tumors [7, 11], for the accuracy in the IMRT treatment of prostate cancer. The mean variations of the bony structures varied by only 0.9 mm in anterior-posterior direction and 0.2 mm in latero-lateral direction. The mean variations of the prostate could be limited to 1.7 mm in anterior-posterior direction and 0.2 mm in latero-lateral direction. This positioning accuracy allows a highly precision radiation therapy with closer safety margins than in conventional 3D planned radiation therapy. The effectiveness of this device in the dose escalation of prostate cancer is currently under investigation . Publications (* = external co-author) [1] Debus, J., et al., Fractionated stereotactic radiotherapy (FSRT) for optic glioma. Int J Radiat Oncol Biol Phys, 1999. 44(2): p. 243-8. [2] Debus, J., et al., Stereotactic fractionated radiotherapy for chordomas and chondrosarcomas of the skull base. Int J Radiat Oncol Biol Phys, 2000. 47(3): p. 591-6. [3] Fuss, M., et al., Conventionally fractionated stereotactic radiotherapy (FSRT) for acoustic neuromas. Int J Radiat Oncol Biol Phys, 2000. 48(5): p. 1381-7.
Fig.2: Survival of patients with liver metastases after stereotactic single-dose radiation therapy. Survival is significantly dependent on the presence of extrahepatic metastatic disease.
DKFZ 2001: Research Report 1999/2000
259
Research Program Radiological Diagnostics and Therapy
Clinical Cooperation Unit Radiation Oncology
[4] Herfarth, K.K., et al., [First experiences with a noninvasive patient set-up system for radiotherapy of the prostate]. Strahlenther Onkol, 2000. 176(5): p. 217-22.
Up to now, 73 patients with tumors of the skull base and the brain have been treated with carbon ions. The study contained patients with chordomas (n=36) and low grade chondrosarcomas (n=16) of the skull base, adenoid cystic carcinomas (n=8) malignant meningeomas (n=8) and other tumors (n=5). These tumors are known to be relatively radioresistant against conventional photon irradiation. Proton radiotherapy has been shown to improve outcome in chordomas and low grade chondrosarcomas [2] but its availability is limited. In adenoid cystic carcinomas radiation therapy with heavy particles as neutrons results in improved local control rates compared to photon irradiation but causes severe side effects [3]. Malignant meningeomas commonly recur within the former irradiated fields even after high tumor doses. Carbon ion therapy presents a promising therapy option in the management of these tumors.
[5] Herfarth, K.K., et al., Stereotactic Single-Dose Radiation Therapy of Liver Tumors: Results of a Phase I/II Trial. J Clin Oncol, 2001. 19(1): p. 164-170. [6] Lohr, F., et al., Conformal three-dimensional photon radiotherapy for paranasal sinus tumors. Radiother Oncol, 2000. 56(2): p. 227-31. [7] Pirzkall, A., et al., Conformal radiotherapy of challenging paraspinal tumors using a multiple arc segment technique. Int J Radiat Oncol Biol Phys, 2000. 48(4): p. 1197-204. [8] Schulz-Ertner, D., et al., Fractionated stereotactic conformal radiation therapy of brain stem gliomas: outcome and prognostic factors. Radiother Oncol, 2000. 57(2): p. 215-23. [9] Herfarth, K.K., et al., Extracranial stereotactic radiation therapy: set-up accuracy of patients treated for liver metastases. Int J Radiat Oncol Biol Phys, 2000. 46(2): p. 329-35. [10] Herfarth, K.K., et al., Stereotaktische Bestrahlung von Lebermetastasen. Radiologe, 2001. 41: p. 64-68.
Within the feasibility study, median tumor dose was 60 GyE in chordomas and chondrosarcomas. Patients with adenoid cystic carcinomas and malignant meningeomas received fractionated stereotactic photon irradiation at the DKFZ with a median dose of 50.4 g Gy and a carbon ion boost with 18 GyE (6 x 3.0 GyE) to the gross tumor. Feasibility of this new therapy approach has been shown. First results are very promising with a local control rate of 94 % after 1 year [4]. We observed a tumor remission in 6 of 29 patients treated for chordoma indicating that carbon ion therapy is effective in these tumors (figure 1). Tumor regression in chordomas is a finding which is rarely reported in literature after any kind of radiation therapy. Besides, active beam delivery using raster scanning allows for highly conformal dose distributions and therefore result in an optimal sparing of neighbouring normal tissue. The low toxicity rate allows further dose escalation. As a consequence the total tumor dose has been escalated from 60 GyE to 70 GyE for chordomas and chondrosarcomas in the following phase II study which has been activated in November 2000.
[11] Lohr, F., et al., Noninvasive patient fixation for extracranial stereotactic radiotherapy. Int J Radiat Oncol Biol Phys, 1999. 45(2): p. 521-7.
Carbon Ion Radiotherapy D. Schulz-Ertner,C. Thilmann, J. Debus In cooperation with: Prof. M. Wannenmacher, Dept. of Radiation Oncology, University of Heidelberg; Prof. G. van Kaick, Div. of Oncol. Diagnostics and Therapy, Prof.. W. Schlegel, Dr. O. Jäkel, Dr. C. Karger, Div. of Medical Physics, DKFZ; Prof. G. Kraft, Dr. T. Haberer, GSI Darmstadt; Dr. W. Enghardt, FZ Rossendorf.
260
The Division of Radiation Oncology started carbon ion radiotherapy at the Gesellschaft für Schwerionenforschung (GSI) Darmstadt within a feasibility study in 1997. Before patient treatments started a radiation unit was built at the heavy ion synchrotron of the GSI and major future directed technical and radiobiological innovations have been implemented. For the first time, tumor conform application of carbon beams was realized by intensity-controlled rasterscanning with pulse-to-pulse energy variation [Haberer T et al. Nucl Inst Phys Res 1993; 330: 296-305]. All patients had 3-dimensional treatment planning including a biological plan optimization using the treatment planning program TRIP [Scholz M et al. Int J Radiat Oncol Biol Phys 1994; 66: 59-75]. A PET camera is used for online beam verification [1].
A new immobilization device developed by Lohr et al 1999 [5] has been tested at GSI and will guarantee the safe irradiation of extracranial tumors. In 2001 a phase I/II study for the treatment of sacral / spinal chordomas and low grade chondrosarcomas will be activated. Furthermore, photon irradiation with a carbon ion boost will be available within a clinical phase I/II study for adenoid cystic carcinomas in 2001. Publications (* = external co-author) [1] *Enghardt W, Debus J, *Haberer et al. The application of PET to quality assurance of heavy ion tumor therapy. Strahlenther Onkol 1999; 175: Suppl II: 33-36. [2] Munzenrider JE, Liebsch NJ. Proton therapy for tumors of the skull base. Strahlenther Onkol 1999; 175 Suppl.: 57-63.
a)
b)
DKFZ 2001: Research Report 1999/2000
Figure 1. Chordoma of the skull base a) prior to RT, b) 3 months after RT
Research Program Radiological Diagnostics and Therapy [3] *Krull A, Schwarz R, Brackrock S et al. Neutron therapy in malignant salivary gland tumors: results at European centers. Recent Res Cancer Res 1998; 150: 88-99. [4] Debus J, *Haberer T, Schulz-Ertner D et al. Carbon ion irradiation of skull base tumors at GSI. First clinical results and future perspectives. Strahlenther Onkol 2000; 176 (5): 211-216 [5] *Lohr F, Debus J, Frank C et al. Noninvasive patient fixation for extracranial stereotactic radiotherapy. Int J Radiat Oncol Biol Phys 1999; 45 (2): 521-527.
New Strategies of Minimally Invasive Tumor Therapy J. Jenne R. Rastert, I. Simiantonakis, M. Moosmann, H. Strohmeyer,P. Huber, M. Hlavac, D. Röder, J. Spoo, I. Zuna, J. Debus In cooperation with: Siemens AG, Medizinische Technik, Erlangen; EDAP/Technomed Lyon, France; J. Vrba, Dept. of Electromagnetic Field, Czech Technical University Prague, Czech Republic; L. Pousek, Centre for BioMedical Engineering, Czech Technical University Prague, Czech Republic; DKFZ: T. Haase, M. Rheinwald, H. Sinn
The aim of this group is the development of new minimal invasive techniques for local tumor therapy.
Ultrasound therapy and first patient treatment with MRI-guided focused ultrasound The goal, to treat a patient with invasive breast cancer with a new non-invasive image guided therapy modality, has been achieved in December 2000. Ultrasound as a form of mechanical wave transmission is widely used in almost all medical specialties, mainly for diagnostic purposes. However, interactions of ultrasound with biological tissues are dependent on the acoustic parameters such as peak pressure amplitude and intensity. Increasing pressure and intensity enables either the thermal or the non-thermal therapeutic capabilities. Both therapeutic approaches are characterized by an excellent focusability combined with a high penetration depth, allowing extensive energy densities in deep tissue layers while sparing intermediate tissues. Non-thermal ultrasound shock wave applications have been proven to be successful in clinical lithotripsy, especially for the removal of kidney stones. The side effects in clinical lithotripsy such as local hemorrhage and edema have prompted research to investigate pulsed high-energy ultrasound shock waves (PHEUS) for the treatment of experimental tumors. PHEUS has been shown to cause cytotoxic effects on tumor cells in vitro and in vivo, and to induce rapid onset of ischemia in experimental tumors with subsequent necroses in tumors leading to tumor growth delay [1-3]. The thermal effects of ultrasound are induced by continuous wave high-intensity focused ultrasound (HIFU) allowing for exact temperature distribution inside the body. HIFU penetrates well through soft tissue and can be focused through the intact skin to volumes with dimensions of a few millimeters. The energy absorption in tissue can induce temperature elevations of 70°C to 90°C in the focal spot within a few seconds that instantaneously denaturates protein structures. Because of the sharp thermal gradients the boundaries of the treated volume are sharply demarcated without damage of the
Clinical Cooperation Unit Radiation Oncology overlying or adjacent tissues. In combination with temperature sensitive magnetic resonance imaging (MRI), HIFU therefore is a promising tool for local tumor therapy in all ultrasound accessible sites such as breast, prostate, liver, kidney, head and neck. The major goal of the research was to develop a MRI guided HIFU treatment unit that could be used for the therapy of breast cancer. To this end, experimental and finally a clinical treatment unit was developed [4-7]. The clinical therapy unit consists of a MRI compatible ultrasound applicator including the ultrasound source; a positioning system and a specific MRI coil to optimize imaging of the focal region. Further elements are a supply unit and a workstation controlling the whole unit. The applicator is built up as a bowl with a pot-shaped deepening to accommodate the breast for treatment. In the deepening an ultrasound transparent window allows coupling the ultrasound field into the breast tissue. The ultrasound transducer has a focal length of about 70 mm and operates at a center frequency of 1.7 MHz. To treat the target region the sound source is moved by three linear actuators. These extensible links consist of hydraulically driven linear stepper motors (resolution