Reinhard Wurm

Commissioning of a micro multi-leaf collimator and planning system for stereotactic radiosurgery

PURPOSE A computer controlled micro multi-leaf collimator, m3 mMLC, has been commissioned for conformal, fixed-field radiosurgery applications. Measurements were made to characterise the basic dosimetric properties of the m3, such as leaf transmission, leakage and beam penumbra. In addition, the geometric and dosimetric accuracy of the m3 was verified when used in conjunction with a BrainSCAN v3.5 stereotactic planning system. MATERIALS AND METHODS The m3 was detachably mounted to a Varian Clinac 2100C accelerator delivering 6 MV X-rays. Leaf transmission, leakage, penumbra and multiple, conformal fixed field dose distributions were measured using calibrated film in solid water. Beam data were collected using a diamond detector in a scanning water tank and planned dose distributions were verified using LiF TLDs and film. A small, shaped phantom was also constructed to confirm field shaping accuracy using portal images. RESULTS Mean transmission through the closed multi-leaves was 1.9 +/- 0.1% and leakage between leaves was 2.8 +/- 0.15%. Between opposing leaves abutting along the central beam-axis transmission was approximately 15 +/- 3%, but was reduced to a mean of 4.5 +/- 0.6% by moving the abutmen position 4.5 cm off-axis. Beam penumbrae were effectively constant as a function of increasing square field size and asymmetric fields and was seen to vary non-linearly when shaped to diagonal, straight edges. TMR, OAR and relative output beam data measurements of circular m3 fields were comparable to conventional, circular stereotactic collimators. Multiple, conformal field dose distributions were calculated with good spatial and dosimetric accuracy, with the planned 90% isodose curves agreeing with measurements to within 1-2 mm and to +/- 3% at isocentre. Portal films agreed with planned beams eye-view field shaping to within 1 mm. CONCLUSIONS The m3 micro multi-leaf collimator is a stable, high precision field-shaping device suitable for small-field, radiosurgery applications. Dose distributions can be accurately calculated by a planning system using only a few beam data parameters.

Prediction of normal-tissue tolerance to radiotherapy from in-vitro cellular radiation sensitivity.

The success of radiotherapy depends on the total radiation dose, which is limited by the tolerance of surrounding normal tissues. Since there is substantial variation among patients in normal-tissue radiosensitivity, we have tested the hypothesis that in-vitro cellular radiosensitivity is correlated with in-vitro normal-tissue responses. We exposed skin fibroblast cell lines from six radiation-treated patients to various doses of radiation and measured the proportions surviving. There was a strong relation between fibroblast sensitivity in vitro and normal-tissue reactions, especially acute effects. Assessment of radiosensitivity could lead to improved tumour cure rates by enabling radiation doses to be tailored to the individual.

Image guided respiratory gated hypofractionated Stereotactic Body Radiation Therapy (H-SBRT) for liver and lung tumors: Initial experience

To evaluate our initial experience with image guided respiratory gated H-SBRT for liver and lung tumors. The system combines a stereoscopic x-ray imaging system (ExacTrac® X-Ray 6D) with a dedicated conformal stereotactic radiosurgery and radiotherapy linear accelerator (Novalis) and ExacTrac® Adaptive Gating for dynamic adaptive treatment. Moving targets are located and tracked by x-ray imaging of implanted fiducial markers defined in the treatment planning computed tomography (CT). The marker position is compared with the position in verification stereoscopic x-ray images, using fully automated marker detection software. The required shift for a correct, gated set-up is calculated and automatically applied. We present our acceptance testing and initial experience in patients with liver and lung tumors. For treatment planning CT and Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) as well as magnetic resonance imaging (MRI) taken at free breathing and expiration breath hold with internal and external fiducials present were used. Patients were treated with 8–11 consecutive fractions to a dose of 74.8–79.2 Gy. Phantom tests demonstrated targeting accuracy with a moving target to within ±1 mm. Inter- and intrafractional patient set-up displacements, as corrected by the gated set-up and not detectable by a conventional set-up, were up to 30 mm. Verification imaging to determine target location during treatment showed an average marker position deviation from the expected position of up to 4 mm on real patients. This initial evaluation shows the accuracy of the system and feasibility of image guided real-time respiratory gated H-SBRT for liver and lung tumors.

123I-IMT SPECT and 1HMR-Spectroscopy at 3.0T in the Differential Diagnosis of Recurrent or Residual Gliomas: A Comparative Study

The aim of this investigation was to compare two current non-invasive modalities, single photon emission tomography (SPECT) using 123-iodine-α-methyl tyrosine (123I-IMT) and single-voxel proton magnetic resonance spectroscopy (1H-MRS) at 3.0 T, with regard to their ability to differentiate between residual/recurrent tumors and treatment-related changes in patients pretreated for glioma. The patient population comprised 25 patients in whom recurrent glioma was suspected based on MR imaging. SPECT imaging started 10 min after iv. injection of 300–370 MBq 123I-IMT and was performed using a triple-head system. The IMT uptake was calculated semiquantitatively using regions-of-interest. 1H-MRS was performed at 3.0 T using the single-volume point-resolved spectroscopy (PRESS) technique. Guided by MR imaging volumes-of-interest for spectroscopy were placed into the suspected lesions. Signal intensities of choline-containing compounds (Cho), creatine and phosphocreatine (Cr), and N-acetylaspartate (NAA) were obtained. When using the cut-off of 1.62 for 123I-IMT uptake, the sensitivity, specificity, and accuracy of the 123I-IMT SPECT were 95, 100 and 96%, respectively. For 1H-MRS, the sensitivity, specificity and accuracy were 89, 83 and 88%, respectively, based both on the metabolic ratios of Cho/Cr and Cho/NAA as tumor criterion with cut-off values of 1.11 and 1.17, respectively. In conclusion, 123I-IMT SPECT yielded more favorable results compared to 1H-MRS at distinguishing recurrent and/or residual glioma from post-therapeutic changes and may be particularly valuable when the evaluation of tumor extent is necessary.

Comparison of dynamic contrast-enhanced MRI with WHO tumor grading for gliomas

Abstract.Assessment of vascular proliferation as an important grading criterion has been employed in both the histologic and the radiologic characterization of gliomas with encouraging results. Perfusion in gliomas can be measured by dynamic contrast-enhanced magnetic resonance imaging (dMRI). The goal of this study was to develop a model for simultaneously quantifying the fractional volumes of different tissue compartments of gliomas by dMRI. A modified method for evaluating dynamic contrast-enhanced MR images is presented which simultaneously determines the fractional vascular, interstitial, and cellular volumes of gliomas. This method differs from techniques used in other studies in that it is based on a three-compartment model: a single blood compartment and two interstitial ones. The fractional volume maps are compared with the WHO glioma grading. The results show the method to be feasible. Using cerebral blood volume (CBV), dMRI grading showed a correspondence with WHO grading in 83% of the cases (20/24 gliomas WHO grades II–IV). The use of interstitial volume maps can also be helpful, for instance, in differentiating gliomas from other brain tumors. As a supplement to conventional MRI, dynamic MR techniques thus provide a useful tool for improving in vivo glioma characterization.

Cellular radiosensitivity and dna damage in primary human fibroblasts

PURPOSE To evaluate the relationship between radiation-induced cell survival and DNA damage in primary human fibroblasts to decide whether the initial or residual DNA damage levels are the more predictive of normal tissue cellular radiosensitivity. METHODS AND MATERIALS Five primary human nonsyndromic and two primary ataxia telangiectasia fibroblast strains grown in monolayer were studied. Cell survival was assessed by clonogenic assay. Irradiation was given at high dose rate (HDR) 1-2 Gy/min. DNA damage was measured in stationary phase cells and expressed as fraction released from the well by pulsed-field gel electrophoresis (PFGE). For initial damage, cells were embedded in agarose and irradiated at HDR on ice. Residual DNA damage was measured in monolayer by allowing a 4-h repair period after HDR irradiation. RESULTS Following HDR irradiation, cell survival varied between SF2 0.025 to 0.23. Measurement of initial DNA damage demonstrated linear induction up to 30 Gy, with small differences in the slope of the dose-response curve between strains. No correlation between cell survival and initial damage was found. Residual damage increased linearly up to 80 Gy with a variation in slope by a factor of 3.2. Cell survival correlated with the slope of the dose-response curves for residual damage of the different strains (p = 0.003). CONCLUSION The relationship between radiation-induced cell survival and DNA damage in primary human fibroblasts of differing radiosensitivity is closest with the amount of DNA damage remaining after repair. If assays of DNA damage are to be used as predictors of normal tissue response to radiation, residual DNA damage provides the most likely correlation with cell survival.

Novalis frameless image-guided noninvasive radiosurgery: initial experience.

OBJECTIVETo evaluate our initial experience with Novalis (BrainLAB, Heimstetten, Germany) frameless image-guided noninvasive radiosurgery. METHODSThe system combines the dedicated Novalis linear accelerator with ExacTrac X-Ray 6D, an infrared camera and a kilovolt stereoscopic x-ray imaging system, a noninvasive mask system, and ExacTrac robotics for patient positioning in six degrees of freedom. Reference cranial skeletal structures are radiographically imaged and automatically fused to digital reconstructed radiographs calculated from the treatment planning computed tomographic scan to find the target position and accomplish automatic real-time tracking before and during radiosurgery. We present the acceptance testing and initial experience in 15 patients with 19 intracranial lesions treated between December 2005 and June 2006 at the Charité by frameless image-guided radiosurgery with doses between 12 and 20 Gy prescribed to the target-encompassing isodose. RESULTSPhantom tests showed an overall system accuracy of 1.04 ± 0.47 mm, with an average in-plane deviation of 0.02 ± 0.96 mm for the x-axis and 0.02 ± 0.70 mm for the y-axis. After infrared-guided patient setup of all patients, the overall average translational deviation determined by stereoscopic x-ray verification was 1.5 ± 1.3 mm, and the overall average rotational deviation was 1.0 ± 0.8 degree. The data used for radiosurgery, after stereoscopic x-ray verification and correction, demonstrated an overall average setup error of 0.31 ± 0.26 mm for translation and 0.26 ± 0.23 degree for rotation. CONCLUSIONThis initial evaluation demonstrates the system accuracy and feasibility of Novalis image-guided noninvasive radiosurgery for intracranial benign and malignant lesions.

Contribution of 68Ga-DOTATOC PET/CT to Target Volume Delineation of Skull Base Meningiomas Treated With Stereotactic Radiation Therapy

PURPOSE To investigate the potential impact of 68Ga-DOTATOC positron emission tomography (68Ga-DOTATOC-PET) in addition to magnetic resonance imaging (MRI) and computed tomography (CT) for retrospectively assessing the gross tumor volume (GTV) delineation of meningiomas of the skull base in patients treated with fractionated stereotactic radiation therapy (FSRT). METHODS AND MATERIALS The study population consisted of 48 patients with 54 skull base meningiomas, previously treated with FSRT. After scans were coregistered, the GTVs were first delineated with MRI and CT data (GTVMRI/CT) and then by PET (GTVPET) data. The overlapping regions of both datasets resulted in the GTVcommon, which was enlarged to the GTVfinal by adding volumes defined by only one of the complementary modalities (GTVMRI/CT-added or GTVPET-added). We then evaluated the contribution of conventional imaging modalities (MRI, CT) and 68Ga-DOTATOC-PET to the GTVfinal, which was used for planning purposes. RESULTS Forty-eight of the 54 skull base lesions in 45 patients showed increased 68Ga-DOTATOC uptake and were further analyzed. The mean GTVMRI/CT and GTVPET were approximately 21 cm3 and 25 cm3, with a common volume of approximately 15 cm3. PET contributed a mean additional GTV of approximately 1.5 cm3 to the common volume (16%±34% of the GTVcommon). Approximately 4.5 cm3 of the GTVMRI/CT was excluded from the contribution to the common volume. The resulting mean GTVfinal was significantly smaller than both the GTVMRI/CT and the GTVPET. Compared with the initial GTVMRI/CT, the addition of 68Ga-DOTATOC-PET resulted in more than 10% modification of the size of the GTVfinal in 32 (67%) meningiomas CONCLUSIONS 68Ga-DOTATOC-PET/CT seems to improve the target volume delineation in skull base meningiomas, often leading to a reduction of GTV compared with results from conventional imaging (MRI and CT).

Aktuelle und zukünftige Strategien in der interdisziplinären Therapie von Medulloblastomen, supratentoriellen PNET und intrakraniellen Keimzelltumoren im Kindesalter

Hintergrund Die Chancen auf Heilung haben sich beim Medulloblastom und bei intrakraniellen Keimzelltumoren im Kindesalter in den letzten Jahrzehnten durchgreifend verbessert. So werden heute langfristige Überlebensraten von 60–80% bzw. mehr als 90% erreicht. Das seltene Vorkommen und die Notwendigkeit ärztlicher Erfahrung in der Steuerung der Therapie und ihrer Nebenwirkungen auf hohem Niveau haben dazu geführt, dass heute über 90% der Kinder innerhalb von nationalen und internationalen Studien behandelt werden, um eine ständige Verbesserung der Resultate zu erreichen. Die Weiterentwicklung operativer Verfahren ermöglicht eine zunehmend bessere und schonendere Resektion von Hirntumoren. Methode: Die systematische Strahlenbehandlung des gesamten Liquorraums ist unverändert wesentlicher Therapiebestandteil bei Medulloblastom, supratentoriellen primitiv neuroektodermalen Tumoren (stPNET) und intrakraniellen Keimzelltumoren. Die Einführung von Qualitätssicherungsprogrammen in der Radioonkologie gewährleistet eine präzise Bestrahlung der Zielvolumina und bildet die Grundvoraussetzung für eine Anhebung der Überlebenszeiten. Ergebnisse: Hyperfraktionierte Strahlenbehandlungen bieten beim Medulloblastom und bei stPNET die Möglichkeit, die wirksame Tumordosis anzuheben, ohne gleichzeitig das Nebenwirkungspotential zu erhöhen. Pilotstudien ergaben eine akzeptable Akuttoxizität und eine ausgezeichnete Tumorkontrolle mit Langzeitüberlebensraten von bis zu 96%. Stereotaktische Bestrahlungstechniken zeigen nach vorläufigen Ergebnissen beim Medulloblastom sowohl eine gute Verträglichkeit als auch vielversprechende Tumorkontrollraten bei Rückfall sowie im Rahmen der Primärtherapie und haben ihren Weg bei persistierendem Resttumor in zukünftige Studienprotokolle gefunden. Die alleinige Bestrahlung der reinen Germinome führt nach reduzierten Dosierungen unverändert zu hohen Heilungsraten (100% SIOP CNS GCT 96). Mit cisplatinhaltigen Chemotherapien lassen sich bei sezernierenden Keimzelltumoren zusammen mit Radiotherapie heute Überlebensraten von 80% erreichen. Chemotherapien sind vor allem beim Medulloblastom mit hohen Risikofaktoren und sezernierenden Keimzelltumoren zu einem festen Bestandteil der interdisziplinären Therapie geworden. Von der Weiterentwicklung chemotherapeutischer Protokolle und der Einführung neuer Substanzen kann eine weitere Verbesserung der bisherigen Behandlungsergebnisse erhofft werden. Schlussfolgerungen: Die Bestrebungen der beteiligten Fachgebiete gehen dahin, Modifikationen der einzelnen Therapiekomponenten innerhalb der interdisziplinären Behandlungskonzepte zu entwickeln, um die bisherigen Ergebnisse weiter zu verbessern. Zukünftig sollten die betroffenen Kinder und Jugendlichen möglichst in die bevorstehende prospektive multizentrische Studie HIT 2000 bzw. in die laufende Studie SIOP CNS GCT 96 aufgenomen werden, um die entsprechenden Ergebnisse zu verbessern und adäquate Entscheidungen für zukünftige optimierte Vorgehensweisen zu ermöglichen.Background The chances for cure in medulloblastoma, supratentorial primitive neuroetodermal tumors (stPNET) and intracranial germ cell tumors have decisively improved within the tast decades. Today long-term survival in the range between 60% and 80% and more than 90%, respectively, can be achieved. The low incidence of brain tumors in childhood and the necessity for optimal patient care has led to the fact that more than 90% of children are treated within national and international controlled studies today in order to assure a constant improvement of therapeutic outcome. Recent developments in neurosurgery achieved complete tumor resections in the majority of children at a low risk for morbidity and mortality. Methods: Systemic irradiation of neuroaxis is an essential part in the management of medulloblastoma, stPNET and intracranial germ cell tumors. The introduction of quality assurance programs in radiooncology assures a precise radiotherapy of target volumes and is a prerequisite to improve survival. Results: Hyperfractionated radiotherapy has the potential of increasing dose to tumor more safely without increasing the risk for late adverse effects. Pilot studies revealed excellent tumor control in medulloblastoma with acceptable acute toxicity and a long-term survival of up to 96%. In medulloblastoma stereotactic radiation techniques reveal an acceptable toxicity and promising results in tumor control in recurrent disease or as primary treatment. They are now part of future treatment protocols in case of persisting residual tumor. Radiotherapy alone in pure germinoma is continuously yielding high cure rates. In secreting germ cell tumors cisplatin containing chemotherapies in conjunction with radiotherapy achieve a long-term survival rate of 80% today. Especially in high risk medulloblastoma and secreting germ cell tumors chemotherapies are playing an increasingly important role in the interdisciplinary management. It can be expected that future developments of chemotherapeutic protocols and the introduction of new cytostatic substances will further improve the therapeutic outcome. Conclusions: The therapeutic endeavors of all those caring for children are aiming to study modifications of the therapeutic components in the interdisciplinary approach in order to optimize the therapeutic strategies. In future the affected children and young adolescents should be accrued for the forthcoming cooperative, prospective trial HIT 2000 and ongoing trial SIOP CNS GCT 96, respectively, in order to provide the body of data supporting the selection of novel and optimized approaches for future treatment strategies.

Intraindividual Comparison of Conventional Three-Dimensional Radiotherapy and Intensity Modulated Radiotherapy in the Therapy of Locally Advanced Non-Small Cell Lung Cancer

Background: Local failure is the one of the most frequent cause of tumor related death in locally advanced non-small cell lung cancer (LAD-NSCLC). Dose escalation has the promise of increased loco-regional tumor control but is limited by the tolerances of critical organs. Patients and Methods: To evaluate the potential of IMRT in comparison to conventional three-dimensional conformal planning (3DCRT) dose constraints were defined: Maximum dose (Dmax) to spinal cord < 48 Gy, mean lung dose ≤ 24 Gy, Dmax esophagus > 70 Gy in not more than 5 cm of the total length. For ten patients two plans were compared: (1) 3DCRT with 5 weekly fractions (SD) of 2 Gy to a total dose (TD) of 50 Gy to the planning target volume of second order (PTV2). If the tolerance of the critical organs was not exceeded, patients get a boost plan with a higher TD to the PTV1. (2) IMRT: concomitant boost with 5 weekly SD of 2 Gy (PTV1) and 1.5 Gy to a partial (p)PTV (pPTV=PTV2 ⌒ PTV1) to a TD of 51 Gy to the pPTV and 68 Gy to the PTV1. If possible, patients get a boost plan to the PTV1 with 5 weekly SD of 2 Gy to the highest possibly TD. Results: Using 3DCRT, 3/10 patients could not be treated with TD > 50 Gy, but 9/10 patients get higher TD by IMRT. TD to the PTV1 could be escalated by 16% on average. The use of non-coplanar fields in IMRT lead to a reduction of the irradiated lung volume. There is a strong correlation between physical and biological mean lung doses. Conclusion: IMRT gives the possibility of further dose escalation without an increasing mean lung dose especially in patients with large tumors.Hintergrund: Lokale Rezidive sind eine häufige Todesursache bei Patienten mit lokal fortgeschrittenen nichtkleinzelligen Bronchialkarzinomen (LAD-NSCLC). Dosiseskalation verspricht hier eine Verbesserung der lokalen Kontrolle, ist aber limitiert durch die Toleranz der Nachbarstrukturen. Patienten und Methoden: Um das Potential der IMRT im Vergleich zur konventionellen 3-D-Planung herauszuarbeiten, wurden folgende Dosis-Volumen-Vorgaben definiert: Maximale Dosis (Dmax) des Myelons < 48 Gy, mittlere Lungendosis (MLD) ≤ 24 Gy, Dmax des Ösophagus > 70 Gy in ≤ 5 cm der Gesamtlänge. Für zehn Patienten mit LAD-NSCLC wurden verglichen: 1. 3DCRT mit fünf wöchentlichen Einzeldosen (ED) von 2 Gy bis zu einer Gesamtdosis (GD) von 50 Gy für das Planungszielvolumen zweiter Ordnung (PTV2). Wenn die Toleranz der umliegenden Gewebe dies zuließ, erhielten die Patienten einen Boostplan für das PTV1. 2. IMRT: Concomitant Boost mit fünf söchentlichen ED von 2 Gy für das PTV1 und 1,5 Gy für das partielle PTV (pPTV=PTV2 ⌒ PTV1) bis zu einer GD von 51 Gy im pPTV und 68 Gy im PTV1. Falls die Belastung des Normalgewebes dies erlaubte, erfolgte ein Boostplan für das PTV1 mit fünf wöchentlichen ED von 2 Gy bis zur höchstmöglichen GD. Ergebnisse: Konventionell konnten 3/10 Patienten mit GD > 50 Gy behandelt werden – mittels IMRT konnten bei 9/10 Patienten höhere Dosen appliziert werden. Im PTV1 konnte im Mittel eine Dosiseskalation von 16% erreicht werden. Besonders Patienten mit großen Tumoren profitierten von der IMRT. Die Verwendung nonkoplanarer Techniken führte zur Verringerung der Dosis innerhalb des kritischen Lungenvolumens. Die physikalischen mittleren Lungendosen waren hoch korreliert mit den biologisch gewichteten mittleren Lungendosen. Schlussfolgerung: Im Vergleich zur 3DCRT ermöglicht die IMRT eine Dosiseskalation in der Behandlung von LAD-NSCLC ohne Erhöhung der mittleren Lungendosis. Von der Technik profitieren insbesondere Patienten mit größeren Tumoren.