Reinhold Graf

Regional Hyperthermia in Conjunction with Definitive Radiotherapy against Recurrent or Locally Advanced Prostate Cancer T3 pN0 M0

Background and Purpose:Since long-term results of the standard treatment of locally advanced or recurrent prostatic carcinoma are unsatisfactory, the role for additional regional hyperthermia was evaluated in a phase I/II study.Patients and Methods:From 08/1996 to 03/2000, 22 patients were treated by a standard irradiation regimen (68.4 Gy) in combination with regional hyperthermia (weekly, five to six times), and five of 22 patients received short-term (neoadjuvant) hormonal treatment. Of these, 15 patients had primary prostatic carcinoma T3 pN0 M0 and seven a histologically confirmed local recurrence after radical prostatectomy. Feasibility of hyperthermia, and acute/late toxicity as well as long-term follow-up (prostate- specific antigen [PSA] control, overall survival) were analyzed. Clinical endpoints were correlated with thermal parameters.Results:Mean maximum temperatures along the urethra of 41.4 °C (41.0 °C for the recurrences), and mean T90 values of 40.7 °C could be achieved. Severe acute toxicity of grade 3 occurred at the rectum in three, at the urethra in four, at the intestine in one, and a burn induced by hyperthermia in one of 22 patients. Late toxicity was only observed rectally in one patient (grade 3) and at the urethra in two patients (grade 2). There was no correlation between thermal parameters and any toxicity. The survival curves showed a PSA control for primary prostatic carcinoma > 50% after 6 years, but no long-term PSA control for the recurrences. Overall survival after 6 years was 95% for primary carcinoma, and 60% for the recurrences. There was a clear correlation between higher temperatures or thermal doses with long-term PSA control.Conclusion:Regional hyperthermia might be a low-toxicity approach to increase PSA control of common treatment schedules. Further evaluation, in particular employing improved hyperthermia technology, is worthwhile.Hintergrund und Ziel:Die Langzeitergebnisse der Standardtherapie beim lokal fortgeschrittenen oder rezidivierten Prostatakarzinom sind unbefriedigend. Daher wurde eine zusätzliche regionale Hyperthermie in einer Phase-I/II-Studie evaluiert.Patienten und Methodik:Von 08/1996 bis 03/2000 wurden 22 Patienten mit einer Standardradiotherapie von 68,4 Gy in Kombination mit regionaler Hyperthermie (wöchentlich, fünf bis sechs Sitzungen) behandelt. Bei fünf von 22 Patienten wurde eine neoadjuvante Hormonbehandlung durchgeführt. Bei 15 Patienten lag ein primäres Prostatakarzinom T3pN0M0 vor; sieben Patienten hatten ein histologisch bestätigtes Lokalrezidiv nach radikaler Prostatektomie. Geprüft wurden die Durchführbarkeit der Hyperthermie, die akute und späte Toxizität sowie die Langzeitkontrolle (PSA-Kontrolle [prostataspezifisches Antigen], Gesamtüberleben). Die klinischen Endpunkte wurden mit thermischen Parametern korreliert.Ergebnisse:Es konnten mittlere Maximaltemperaturen entlang der Urethra von 41,4 °C (41,0 °C für die Rezidive) sowie mittlere T90 von 40,7 °C erreicht werden. Schwere akute Nebenwirkungen vom Grad 3 traten am Rektum bei drei, an der Urethra bei vier, am Dünndarm bei einem sowie durch Hyperthermie bedingt (Verbrennung) bei einem von 22 Patienten auf. Spätfolgen wurden nur bei einem Patienten am Rektum (Grad 3) und bei zwei Patienten an der Urethra (Grad 2) festgestellt. Es bestand keine Korrelation zwischen thermischen Parametern und irgendeiner Toxizität. Die Überlebenskurven zeigten eine PSA-Kontrolle von > 50% beim primären Prostatakarzinom nach 6 Jahren, jedoch keine Langzeit-PSA-Kontrolle bei den Rezidiven. Das Gesamtüberleben betrug nach 6 Jahren 95% für die primären Prostatakarzinome und 60% für die Rezidive. Es fand sich eine deutliche Korrelation zwischen hohen Temperaturen bzw. thermischen Dosen und der langfristigen PSA-Kontrolle.Schlussfolgerung:Die regionale Hyperthermie könnte eine gut verträgliche Zusatztherapie sein, um die PSA-Kontrolle von üblichen Therapieschemata zu verbessern. Hier ist eine weitere Evaluation sinnvoll, insbesondere auch unter Anwendung verbesserter Hyperthermietechnologien.

Potentials of on-line repositioning based on implanted fiducial markers and electronic portal imaging in prostate cancer radiotherapy

BackgroundTo evaluate the benefit of an on-line correction protocol based on implanted markers and weekly portal imaging in external beam radiotherapy of prostate cancer. To compare the use of bony anatomy versus implanted markers for calculation of setup-error plus/minus prostate movement. To estimate the error reduction (and the corresponding margin reduction) by reducing the total error to 3 mm once a week, three times per week or every treatment day.Methods23 patients had three to five, 2.5 mm Ø spherical gold markers transrectally inserted into the prostate before radiotherapy. Verification and correction of treatment position by analysis of orthogonal portal images was performed on a weekly basis. We registered with respect to the bony contours (setup error) and to the marker position (prostate motion) and determined the total error. The systematic and random errors are specified. Positioning correction was applied with a threshold of 5 mm displacement.ResultsThe systematic error (1 standard deviation [SD]) in left-right (LR), superior-inferior (SI) and anterior-posterior (AP) direction contributes for the setup 1.6 mm, 2.1 mm and 2.4 mm and for prostate motion 1.1 mm, 1.9 mm and 2.3 mm. The random error (1 SD) in LR, SI and AP direction amounts for the setup 2.3 mm, 2.7 mm and 2.7 mm and for motion 1.4 mm, 2.3 mm and 2.7 mm. The resulting total error suggests margins of 7.0 mm (LR), 9.5 mm (SI) and 9.5 mm (AP) between clinical target volume (CTV) and planning target volume (PTV). After correction once a week the margins were lowered to 6.7, 8.2 and 8.7 mm and furthermore down to 4.9, 5.1 and 4.8 mm after correcting every treatment day.ConclusionProstate movement relative to adjacent bony anatomy is significant and contributes substantially to the target position variability. Performing on-line setup correction using implanted radioopaque markers and megavoltage radiography results in reduced treatment margins depending on the online imaging protocol (once a week or more frequently).

Residual Translational and Rotational Errors after kV X-Ray Image-Guided Correction of Prostate Location Using Implanted Fiducials

Purpose:To evaluate the residual errors and required safety margins after stereoscopic kilovoltage (kV) X-ray target localization of the prostate in image-guided radiotherapy (IGRT) using internal fiducials.Patients and Methods:Radiopaque fiducial markers (FMs) have been inserted into the prostate in a cohort of 33 patients. The ExacTrac/Novalis Body™ X-ray 6d image acquisition system (BrainLAB AG, Feldkirchen, Germany) was used. Corrections were performed in left-right (LR), anterior-posterior (AP), and superior-inferior (SI) direction. Rotational errors around LR (x-axis), AP (y) and SI (z) have been recorded for the first series of nine patients, and since 2007 for the subsequent 24 patients in addition corrected in each fraction by using the Robotic Tilt Module™ and Varian Exact Couch™. After positioning, a second set of X-ray images was acquired for verification purposes. Residual errors were registered and again corrected.Results:Standard deviations (SD) of residual translational random errors in LR, AP, and SI coordinates were 1.3, 1.7, and 2.2 mm. Residual random rotation errors were found for lateral (around x, tilt), vertical (around y, table), and longitudinal (around z, roll) and of 3.2°, 1.8°, and 1.5°. Planning target volume (PTV)-clinical target volume (CTV) margins were calculated in LR, AP, and SI direction to 2.3, 3.0, and 3.7 mm. After a second repositioning, the margins could be reduced to 1.8, 2.1, and 1.8 mm.Conclusion:On the basis of the residual setup error measurements, the margin required after one to two online X-ray corrections for the patients enrolled in this study would be at minimum 2 mm. The contribution of intrafractional motion to residual random errors has to be evaluated.ZusammenfassungZiel:Der residuale Lagerungsfehler und die erforderlichen Sicherheitsabstande in der bildgestutzten Lokalisation und Positionskorrektur der Prostata sollten ermittelt werden.Patienten und Methodik:In einer Gruppe von 33 Patienten wurden rontgendichte Marker in die Prostata implantiert. Die Autoren setzten das rontgenbasierte und automatisierte Positionierungs- und Verifikationssystem ExacTrac/Novalis Body™ (BrainLAB AG, Feldkirchen) ein. Fur die erste Serie von neun Patienten erfolgten tagliche Korrekturen des initalen Translationsfehlers in mediolateraler (ML), anteroposteriorer (AP) und superoinferiorer (SI) Richtung. Rotationsfehler um die seitliche (x), vertikale (y) und longitudinale Achse (z) wurden aufgezeichnet und seit 2007 fur die ubrigen 24 Patienten unter Verwendung des Robotic Tilt Module™ und der Varian Exact Couch™ vor jeder Fraktion ausgeglichen. Nach der Positionierung erfolgte eine Verifikation der Patientenposition mittels stereoskopischer Rontgenkontrollaufnahmen. Noch bestehende residuale Fehler wurden aufgezeichnet und erneut winkelgetreu korrigiert.Ergebnisse:Der residuale translationale Fehler betrug in LR, AP und SI (1 Standardabweichung [SD]) 1,3, 1,7 und 2,2 mm. Ermittelt wurden residuale Rotationsfehler (1 SD) um x, y und z von 3,2°, 1,8° und 1,5°. Die erforderlichen Sicherheitsabstande zwischen klinischem Zielvolumen (CTV) und Planungszielvolumen (PTV) wurden in ML, AP und SI mit 2,3, 3,0 und 3,7 mm berechnet. Nach einem zweiten Korrekturschritt konnten diese Sicherheitsabstande auf 1,8, 2,1 und 1,8 mm verringert werden.Schlussfolgerung:Auf der Grundlage der nach ein (oder zwei) Lagerungskorrekturen verbleibenden Restfehler der Patienten dieser Studie ist fur das PTV ein Sicherheitsabstand von mindestens 2 mm zum CTV erforderlich. Der Beitrag der intrafraktionellen Bewegung der Prostata fur den Lokalisationsfehler verbleibt das Thema weiterer Untersuchungen.

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).

Interfraction rotation of the prostate as evaluated by kilovoltage X-ray fiducial marker imaging in intensity-modulated radiotherapy of localized prostate cancer

To quantify the daily rotation of the prostate during a radiotherapy course using stereoscopic kilovoltage (kV) x-ray imaging and intraprostatic fiducials for localization and positioning correction. From 2005 to 2009, radio-opaque fiducial markers were inserted into 38 patients via perineum into the prostate. The ExacTrac/Novalis Body X-ray 6-day image acquisition system (ET/NB; BrainLab AG, Feldkirchen, Germany) was used to determine and correct the target position. During the first period in 10 patients we recorded all rotation errors but used only Y (table) for correction. For the next 28 patients we used for correction all rotational coordinates, i.e., in addition Z (superior-inferior [SI] or roll) and X (left-right [LR] or tilt/pitch) according to the fiducial marker position by use of the Robotic Tilt Module and Varian Exact Couch. Rotation correction was applied above a threshold of 1° displacement. The systematic and random errors were specified. Overall, 993 software-assisted rotational corrections were performed. The interfraction rotation errors of the prostate as assessed from the radiodense surrogate markers around the three axes Y, Z, and X were on average 0.09, -0.52, and -0.01° with standard deviations of 2.01, 2.30, and 3.95°, respectively. The systematic uncertainty per patient for prostate rotation was estimated with 2.30, 1.56, and 4.13° and the mean random components with 1.81, 2.02, and 3.09°. The largest rotational errors occurred around the X-axis (pitch), but without preferring a certain orientation. Although the error around Z (roll) can be compensated on average by a transformation with 4 coordinates, a significant error around X remains and advocates the full correction with 6 coordinates. Rotational errors as assessed via daily stereoscopic online imaging are significant and dominate around X. Rotation possibly degrades the dosimetric coverage of the target volume and may require suitable strategies for correction.

Appropriate patient instructions can reduce prostate motion

BackgroundInterfraction prostate motion must be compensated by increased safety margins. If filling status of rectum and bladder is constant, motion should be reduced. We attempted to reduce interfraction motion errors by proper patient instruction.MethodIn 38 patients pairs of radio-opaque fiducial markers were implanted prior to definitive radiotherapy. Patients were positioned either according to skin marks or infrared body marker. We measured prostate displacement, i.e. pelvic bones versus intraprostatic marker position, via ExacTrac (two orthogonal radiographies) in 1252 fractions. Systematic and random setup and displacement errors were determined and safety margins estimated.ResultsIn our study interfraction prostate displacement is < 1 mm in RL direction, and < 2 mm in AP and SI direction. Systematic errors are slightly below random errors (< 1.5 mm). Positioning according skin marks results in higher inaccuracies of ±1.5 – 2 mm in RL and ±2 – 2.5 mm in AP/SI direction.ConclusionsIn case of appropriate patient instructions (constant organ filling) the positioning via bone fusion requires CTV-PTV margins of 2 mm in RL, 4 mm in AP, and 5 mm in SI direction. Studies without any description of patient instruction found much higher margins of > 1 cm in AP and SI direction.

Magnetic resonance imaging, computed tomography, and 68Ga-DOTATOC positron emission tomography for imaging skull base meningiomas with infracranial extension treated with stereotactic radiotherapy - a case series

IntroductionMagnetic resonance imaging (MRI) and computed tomography (CT) with 68Ga-DOTATOC positron emission tomography (68Ga-DOTATOC-PET) were compared retrospectively for their ability to delineate infracranial extension of skull base (SB) meningiomas treated with fractionated stereotactic radiotherapy.MethodsFifty patients with 56 meningiomas of the SB underwent MRI, CT, and 68Ga-DOTATOC PET/CT prior to fractionated stereotactic radiotherapy. The study group consisted of 16 patients who had infracranial meningioma extension, visible on MRI ± CT (MRI/CT) or PET, and were evaluated further. The respective findings were reviewed independently, analyzed with respect to correlations, and compared with each other.ResultsWithin the study group, SB transgression was associated with bony changes visible by CT in 14 patients (81%). Tumorous changes of the foramen ovale and rotundum were evident in 13 and 8 cases, respectively, which were accompanied by skeletal muscular invasion in 8 lesions. We analysed six designated anatomical sites of the SB in each of the 16 patients. Of the 96 sites, 42 had infiltration that was delineable by MRI/CT and PET in 35 cases and by PET only in 7 cases. The mean infracranial volume that was delineable in PET was 10.1 ± 10.6 cm3, which was somewhat larger than the volume detectable in MRI/CT (8.4 ± 7.9 cm3).Conclusions68Ga-DOTATOC-PET allows detection and assessment of the extent of infracranial meningioma invasion. This method seems to be useful for planning fractionated stereotactic radiation when used in addition to conventional imaging modalities that are often inconclusive in the SB region.

Results for local control and functional outcome after linac-based image-guided stereotactic radiosurgery in 190 patients with vestibular schwannoma

Background We assessed local control (LC) and functional outcome after linac-based stereotactic radiosurgery (SRS) for vestibular schwannoma (VS). Methods Between 1998 and 2008, 190 patients with VS were treated with SRS. All patients had tumors <2 cm diameter. Patients received 13.5 Gy prescribed to the 80th isodose at the tumor margin. The primary endpoint was LC. Secondary endpoints were symptomatic control and morbidity. Results Median follow-up was 40 months. LC was achieved in 88% of patients. There were no acute reactions exceeding Grade I. Trigeminal nerve dysfunction was present in 21.6% (n = 41) prior to SRS. After treatment, 85% (n = 155) had no change, 4.4,% (n = 8) had a relief of symptoms, 10.4% (n = 19) had new symptoms. Facial nerve dysfunction was present in some patients prior to treatment, e.g. paresis (12.6%; n = 24) and dysgeusia (0.5%; n = 1). After treatment 1.1% (n = 2) reported improvement and 6.1% (n = 11) experienced new symptoms. Hearing problems before SRS were present in 69.5% of patients (n = 132). After treatment, 62.6% (n = 144) had no change, 10.4% (n = 19) experienced improvement and 26.9% (n = 49) became hearing impaired. Conclusion This series of SRS for small VS provided similar LC rates to microsurgery; thus, it is effective as a non-invasive, image-guided procedure. The functional outcomes observed indicate the safety and effectiveness of linac-based SRS. Patients may now be informed of the clinical equivalence of SRS to microsurgery.

Dose-Escalated Conformal Radiotherapy of Glioblastomas – Results of a Retrospective Comparison Applying Radiation Doses of 60 and 70 Gy

Background: Dose escalated three-dimensional conformal radiotherapy with 70 Gy against glioblastomas was compared retrospectively with the standard scheme of 60 Gy using 2-D-planning. Patients and Methods: In the period from 1994 to 1998, a series of 135 patients with glioblastomas was treated by surgery and postoperative radiotherapy. A conversion from 2-D into 3-D-planning was carried out in 4/1996. The prescribed total dose for the first 65 patients was 60 Gy (group 60). A boost up to 70 Gy was added for the remaining 70 patients (group 70). Results: The median survival time was 8.0 months for group 60 and 8.3 months for group 70. A dependency on the applied dose range was found. The median survival time was 3 months for patients who received a radiation dose of 55 Gy or less, 8.6 months for doses between 56 and 65 Gy, and 9.6 months for patients with a dose between 66 and 75 Gy (p < 0.01). In a multivariate analysis only the performance status maintained significance (p = 0.02) as a prognostic factor, while the dose range reached borderline significance (p = 0.09). Conclusion: No statistically significant survival prolongation was reached despite a dose escalation to 70 Gy.

Intrafraction variations in linac-based image-guided radiosurgery of intracranial lesions.

PURPOSE This study investigated image-guided patient positioning during frameless, mask-based, single-fraction stereotactic radiosurgery of intracranial lesions and intrafractional translational and rotational variations in patient positions. PATIENTS AND METHODS A non-invasive head and neck thermoplastic mask was used for immobilization. The Exactrac/Novalis Body system (BrainLAB AG, Germany) was used for kV X-ray imaging guided positioning. Intrafraction displacement data, obtained by imaging after each new table position, were evaluated. RESULTS There were 269 radiosurgery treatments performed on 190 patients and a total of 967 setups within different angles. The first measured error after each table rotation (mean 2.6) was evaluated (698 measurements). Intrafraction translational errors were (1 standard deviation [SD]) on average 0.8, 0.8, and 0.7mm for the left-right, superior-inferior, and anterior-posterior directions, respectively, with a mean 3D-vector of 1.0mm (SD 0.9mm) and a range from -5mm to +5mm. On average, 12%, 3%, and 1% of the translational deviations exceeded 1, 2, and 3mm, respectively, in the three directions. CONCLUSION The range of intrafraction patient motion in frameless image-guided stereotactic radiosurgery is often not fully mapped by pre- and post-treatment imaging. In the current study, intrafraction motion was assessed by performing measurements at several time points during the course of stereotactic radiosurgery. It was determined that 12% of the intrafraction values in the three dimensions are above 1mm, the usual safety margin applied in stereotactic radiosurgery.