Dirk Böhmer

Magnetic nanoparticles for interstitial thermotherapy - : feasibility, tolerance and achieved temperatures

Background: The concept of magnetic fluid hyperthermia is clinically evaluated after development of the whole body magnetic field applicator MFH® 300F and the magnetofluid MFL 082AS. This new system for localized thermotherapy is suitable either for hyperthermia or thermoablation. The magnetic fluid, composed of iron oxide nanoparticles dispersed in water, must be distributed in the tumour and is subsequently heated by exposing to an alternating magnetic field in the applicator. We performed a feasibility study with 22 patients suffering from heavily pretreated recurrences of different tumour entities, where hyperthermia in conjunction with irradiation and/or chemotherapy was an option. The potential to estimate (by post-implantation analyses) and to achieve (by improving the technique) a satisfactory temperature distribution was evaluated in dependency on the implantation technique. Material and methods: Three implantation methods were established: Infiltration under CT fluoroscopy (group A), TRUS (transrectal ultrasound) – guided implantation with X-fluoroscopy (group B) and intra-operative infiltration under visual control (group C). In group A and B the distribution of the nanoparticles can be planned prior to implantation on the basis of three-dimensional image datasets. The specific absorption rates (SAR in W/kg) can be derived from the particle distribution imaged via CT together with the actual H-field strength (in kA/m). The temperature distribution in the tumour region is calculated using the bioheat-transfer equation assessing a mean perfusion value, which is determined by matching calculated temperatures to direct (invasive or endoluminal) temperature measurements in reference points in or near the target region. Results: Instillation of the magnetic fluid and the thermotherapy treatments were tolerated without or with only moderate side effects, respectively. Using tolerable H-field-strengths of 3.0–6.0 kA/m in the pelvis, up to 7.5 kA/m in the thoracic and neck region and >10.0 kA/m for the head, we achieved SAR of 60–380 W/kg in the target leading to a 40°C heat-coverage of 86%. However, the coverage with ≥42°C is unsatisfactory at present (30% of the target volume in group A and only 0.2% in group B). Conclusion: Further improvement of the temperature distribution is required by refining the implantation techniques or simply by increasing the amount of nanofluid or elevation of the magnetic field strength. From the actual nanoparticle distribution and derived temperatures we can extrapolate, that already a moderate increase of the H-field by only 2 kA/m would significantly improve the 42°C coverage towards 100% (98%). This illustrates the great potential of the nanofluid-based heating technology.

IMPACT OF THE FILLING STATUS OF THE BLADDER AND RECTUM ON THEIR INTEGRAL DOSE DISTRIBUTION AND THE MOVEMENT OF THE UTERUS IN THE TREATMENT PLANNING OF GYNAECOLOGICAL CANCER

PURPOSE Determination of the impact of the filling status of the organs at risk (bladder and rectum) on the uterus mobility and on their integral dose distribution in radiotherapy of gynaecological cancer. METHODS In 29 women suffering from cervical or endometrial cancer two CT scans were carried out for treatment planning, one with an empty bladder and rectum, the second one with bladder and rectum filled. The volumes of the organs at risk were calculated and in 14 patients, receiving a definitive radiotherapy, the position of the uterus within the pelvis was shown using multiplanar reconstructions. After generation of a 3D treatment plan the dose volume histograms were compared for empty and filled organs at risk. RESULTS The mobility for the corpus uteri with/without bladder and rectum filling was in median 7 mm (95%-confidence interval: 3-15 mm) in cranial/caudal direction and 4 mm (0-9 mm) in posterior/anterior direction. Likewise, cervical mobility was observed to be 4 mm (-1-6 mm) mm in cranial/caudal direction. A full bladder led to a mean reduction in organ dose in median from 94-87% calculated for 50% of the bladder volume (P < 0.05, Wilcoxons matched-pairs signed-ranks test). For 66% of the bladder volume the dose could be reduced in median from 78 to 61% (P < 0.005) and for the whole bladder from 42 to 39% (P < 0.005), respectively. No significant contribution of the filling status of the rectum to its integral dose burden was noticed. CONCLUSIONS Due to the mobility of the uterus increased margins between CTV and PTV superiorly, inferiorly, anteriorly and posteriorly of 15, 6 and 9 mm each, respectively, should be used. A full bladder is the prerequisite for an integral dose reduction.

Palliative Strahlentherapie von KnochenmetastasenEine retrospektive Analyse von 176 Patienten

Ziel: Die Effizienz der palliativen Strahlentherapie bei ossärer Metastasierung wird in dieser retrospektiven Studie untersucht. Das Spektrum der den Knochenmetastasen zugrundeliegenden unterschiedlichen Primärtumoren und Lokalisationen wird analysiert. Zusätzlich werden die in dieser retrospektiven Studie eingesetzten Fraktionierungsschemata im Hinblick auf die Palliation (Schmerzremission) analysiert. Dabei soll zwischen globaler Ansprechrate und partieller sowie kompletter Schmerzremission differenziert werden. Patienten und Methode: Diese retrospektive quantitative Analyse umfaßt 176 Patienten, bei denen im Zeitraum von April 1992 bis November 1993 258 Lokalisationen mit Knochenmetastasen bestrahlt wurden. Der prozentuale Anteil ossärer Metastasen im Verhältnis zur Gesamtpatientenzahl, die zugrundeliegenden Primärtumoren, Lokalisationen und unterschiedlichen Fraktionierungsregime wurden quantifiziert. Bei den häufigsten Fraktionierungsregimen und Tumorentitäten wurde die Palliation (Schmerzremission) als globale Ansprechrate und differenziert in Form der partiellen bzw. kompletten Schmerzremission analysiert. Ergebnisse: Knochenmetastasen machten 8% aller bestrahlten Lokalisationen in der Strahlenklinik der Charité innerhalb des 19monatigen Beobachtungszeitraums aus. Es wurden insgesamt 21 unterschiedliche Tumorentitäten bestrahlt. Ossäre Metastasen traten am häufigsten beim Mammakarzinom (49%), Bronchialkarzinom (15%) und Nierenzellkarzinom (6%) auf. Der Prädilektionsort der ossären Metastasen war die Wirbelsäule in 52%. Von den 19 unterschiedlichen Fraktionierungsregimen wurden am häufigsten die folgenden eingesetzt: 4mal 5 Gy (32%), 10mal 3 Gy (18%), 6mal 5 Gy (9%), 7mal 3 Gy (7%), 10mal 2 Gy (5%) und 2mal 8 Gy. Die globalen Ansprechraten betrugen dementsprechend: 72%, 79%, 74%, 76%, 75% und 72%, die kompletten Remissionen: 35%, 32%, 30%, 35%, 33% und 33%. Ein Unterschied zwischen den häufigsten Tumorentitäten sowie den verschiedenen Lokalisationen und der Palliation konnte weder in den globalen Ansprechraten noch in den differenzierteren Endpunkten der partiellen bzw. kompletten Schmerzremissionen quantifiziert werden. Schlußfolgerung: Die verschiedenen Fraktionierungsregime unterscheiden sich nicht signifikant hinsichtlich ihrer Effizienz bei ossären Metastasen. Die Palliation ist in ca. 75% aller Fälle gewährleistet mit einer Rate von 33% kompletten und 42% partiellen Schmerzremissionen. Unter alleiniger Berücksichtigung der Schmerzreduktion rechtfertigen diese Resultate nicht die Empfehlung einer Standardfraktionierung. Aus klinisch pragmatischen Gründen sollten gängige Fraktionierungsschemata wie 10mal 3 Gy über zwei Wochen oder 5mal 4 Gy in einer Woche eingesetzt werden. Neben der Palliation sollte jedoch auch – insbesondere bei Patienten mit längerer Prognose – die Remineralisation als Voraussetzung der Stabilisierung und Frakturprävention und als der einzige objektivierbare Parameter des Strahlentherapieerfolgs in zukünftige prospektive Analysen einfließen.Background: The effect of the palliative irradiation of bone metastases was explored in this retrospective analysis. The spectrum of primary tumor sites, the localization of the bone metastases and the fractionation schedules were analyzed with regard to palliation discriminating total, partial and complete pain response. Patients and Methods: One hundred seventy-six patients are included in this retrospective quantitative study from April 1992 to November 1993. Two hundred fifty-eight localizations of painful bone metastases were irradiated. The percentage of bone metastases of the total irradiated localizations in our department of radiotherapy in the Charité-Hospital, the primary tumor sites, the localizations and the different fractionation schedules were explored. The total, partial and complete pain response was analyzed in the most often used fractionation schedules and by primary tumor sites. Results: Eight per cent of all irradiated localizations in the observation period were bone metastases. There were irradiated bone metastases of 21 different tumor sites. Most of the primary tumor sites were breast cancer (49%), lung cancer (6%) and kidney cancer (16%). The most frequent site of metastases was the vertebral column (52%). The most often used fractination schedules were: 4 × 5 Gy (32%), 10 × 3 Gy (18%), 6 × 5 Gy (9%&), 7 × 3 Gy (7%), 10 × 2 Gy (5%) and 2 × 8 Gy. The total response rates in this fractionation schedules were 72%, 79%, 74%, 76%, 75% and 72%, the complete response rates were 35%, 32%, 30%, 35%, 33% and 33%. There were no significant differences between the most often irradiated primary tumor sites, the most frequent localizations and the palliation with regard to total, partial and complete pain response. Conclusion: There are no differences between the different fractionation schedules with regard to the pain effect of bone metastases. A palliation is ensured in 75% of all cases with a partial response of 42% and complete response of 33%. With regard to pain response these results do not justify a recommendation for a standard fractionation schedule. Current fractionation schedules such as 10 × 3 Gy for 2 weeks or 5 × 4 Gy for 1 week should be used. Another point is the recalcification in the palliative treatment of bone metastases in patients with better prognosis. The recalcification is the basis for stabilization and prevention of fractures. This aspect should be explored in prospective studies.

MRI before and after external beam intensity-modulated radiotherapy of patients with prostate cancer: The feasibility of monitoring of radiation-induced tissue changes using a dynamic contrast-enhanced inversion-prepared dual-contrast gradient echo sequence

PURPOSE To identify and quantify suitable pharmacokinetic MRI parameters for monitoring tissue changes after external beam intensity-modulated radiotherapy of prostate cancer. MATERIAL AND METHODS Six patients with biopsy-proven prostate cancer (initial PSA, 6.0-81.4 ng/ml) underwent MRI at 1.5 T using a combined endorectal/body phased-array coil and a dynamic contrast-enhanced inversion-prepared dual-contrast gradient echo sequence (T1/T2(*)w; 1.65 s temporal resolution). MRI was performed before and immediately after radiotherapy, at 3 months and at 1 year. Perfusion, blood volume, mean transit time, delay, dispersion, interstitial volume, and extraction coefficient were calculated in prostate cancer and normal prostate for all four time points using a sequential 3-compartment model. RESULTS Prostate cancer and normal prostate tissue showed a statistically significant decrease in perfusion (p=0.006, p=0.001) and increase in extraction coefficient (p=0.004, p<0.001). For prostate cancer, there was also a decrease in vascular volume (p=0.034). The other parameters investigated showed no statistically significant changes. Statistically significant differences between prostate cancer and normal prostate tissue were only observed before radiotherapy, when prostate cancer showed significantly higher perfusion (1.84 vs. 0.12 ml/cm(3)min, p=0.028) and a smaller extraction coefficient (0.42 vs. 0.64, p=0.028). CONCLUSIONS Two pharmacokinetic parameters, perfusion and extraction coefficient, appear to be suitable candidates for monitoring the response to percutaneous intensity-modulated radiotherapy of prostate cancer.

The German S3 guideline prostate cancer: aspects for the radiation oncologist.

This report summarizes the relevant aspects of the S3 guideline prostate cancer for the radiation oncologist. Treatment decision and dose prescription are discussed, as well as technical performance of external beam radiotherapy and brachytherapy. The relevant literature is cited to allow an overview of the current recommendations.ZusammenfassungDieser Bericht fasst die relevanten Aspekte der S3-Leitlinie Prostatakarzinom für den Strahlentherapeuten zusammen. Indikationsstellung und Dosisverschreibung werden ebenso diskutiert wie die technische Durchführung der perkutanen Bestrahlung und die Brachytherapie. Die relevante Literatur gibt einen Überblick über die aktuellen Empfehlungen.

Use of EORTC Target Definition Guidelines for Dose-Intensified Salvage Radiation Therapy for Recurrent Prostate Cancer: Results of the Quality Assurance Program of the Randomized Trial SAKK 09/10

PURPOSE Different international target volume delineation guidelines exist and different treatment techniques are available for salvage radiation therapy (RT) for recurrent prostate cancer, but less is known regarding their respective applicability in clinical practice. METHODS AND MATERIALS A randomized phase III trial testing 64 Gy vs 70 Gy salvage RT was accompanied by an intense quality assurance program including a site-specific and study-specific questionnaire and a dummy run (DR). Target volume delineation was performed according to the European Organisation for the Research and Treatment of Cancer guidelines, and a DR-based treatment plan was established for 70 Gy. Major and minor protocol deviations were noted, interobserver agreement of delineated target contours was assessed, and dose-volume histogram (DVH) parameters of different treatment techniques were compared. RESULTS Thirty European centers participated, 43% of which were using 3-dimensional conformal RT (3D-CRT), with the remaining centers using intensity modulated RT (IMRT) or volumetric modulated arc technique (VMAT). The first submitted version of the DR contained major deviations in 21 of 30 (70%) centers, mostly caused by inappropriately defined or lack of prostate bed (PB). All but 5 centers completed the DR successfully with their second submitted version. The interobserver agreement of the PB was moderate and was improved by the DR review, as indicated by an increased κ value (0.59 vs 0.55), mean sensitivity (0.64 vs 0.58), volume of total agreement (3.9 vs 3.3 cm(3)), and decrease in the union volume (79.3 vs 84.2 cm(3)). Rectal and bladder wall DVH parameters of IMRT and VMAT vs 3D-CRT plans were not significantly different. CONCLUSIONS The interobserver agreement of PB delineation was moderate but was improved by the DR. Major deviations could be identified for the majority of centers. The DR has improved the acquaintance of the participating centers with the trial protocol.

The German S3 Guideline Prostate Cancer

This report summarizes the relevant aspects of the S3 guideline prostate cancer for the radiation oncologist. Treatment decision and dose prescription are discussed, as well as technical performance of external beam radiotherapy and brachytherapy. The relevant literature is cited to allow an overview of the current recommendations.ZusammenfassungDieser Bericht fasst die relevanten Aspekte der S3-Leitlinie Prostatakarzinom für den Strahlentherapeuten zusammen. Indikationsstellung und Dosisverschreibung werden ebenso diskutiert wie die technische Durchführung der perkutanen Bestrahlung und die Brachytherapie. Die relevante Literatur gibt einen Überblick über die aktuellen Empfehlungen.

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.

Vergleich unterschiedlicher dreidimensionaler Bestrahlungstechniken bei der lokalen Strahlentherapie des Prostatakarzinoms

ZielVier verschiedene SD-Bestrahlungstechniken wurden hinsichtlich der Dosishomogenität im Targetvolumen und der Dosis-Volumen-Belastung der Risikoorgane in AbhÄngigkeit vom Tumorstadium untersucht.Patienten und MethodeBei 17 Patienten wurden eine 3D-Rotations-, Vier-Felder-, Fünf-Felder- und Sechs-Felder-Technik erstellt. Sechs Patienten wiesen ein Stadium T1N0M0, sieben Patienten ein Stadium T2N0M0 und vier Patienten ein Stadium T3N0M0 auf. Dosiert wurde auf den Referenzpunkt im Isozentrum (100%). Die 95%-Isodose mu\te das Planungszielvolumen umschlie\en. Es wurden bei allen Techniken Multileaf-Kollimatoren verwendet und Dosis-Volumen-Histogramme für das Planungszielvolumen und die Risikoorgane (Blase, Rektum, Hüftköpfe) erstellt und miteinander verglichen. Der Vergleich erfolgte jeweils bei 33%, 50% und 66% Volumen des jeweiligen Risikoorgans.ErgebnisseHinsichtlich der Dosishomogenität im Targetvolumen zeigte sich kein Unterschied. Eine signifikante Differenz wurde bei der Blasenbelastung zwischen der Sechs-Felder- und der Vier-Felder-Technik nur bei 50% Volumenanteil (p = 0,034), zwischen Sechs-Felder- und Rotationstechnik sowie zwischen Fünf-Felder- und Rotationstechnik bei allen Volumenanteilen gesehen. Bei der Belastung des Rektums ergab sich eine signifikante Differenz zwischen der Sechs- und der Vier-Felder-Technik bei T1- und T2-Tumoren sowohl bei 50% (p = 0,033) als auch bei 66% (p = 0,011). Bei den T3-Tumoren ergaben sich hinsichtlich der Rektumbelastung keine signifikanten Unterschiede. Die beste Schonung der Hüftköpfe wurde durch die Rotationstechnik erzielt.Schlu\folgerungBei der kleinvolumigen Bestrahlung der Prostata ist bei T1/2-Tumoren durch die Sechs-Felder-Technik die beste Schonung von Rektum und Blase zu erzielen, bei grö\erem Planungszielvolumen und bei Einschlu\ der SamenblÄschen sollten andere Techniken, wie zum Beispiel eine dreidimensional geplante Vier-Felder-Technik, zur besseren Schonung der Risikoorgane angewendet werden.AbstractPurposeFour different three-dimensional planning techniques for localized radiotherapy of prostate cancer were compared with regard to dose homogeneity within the target volume and dose to organs at risk, dependent upon tumor stage.Patients and MethodsSix patients with stage T1, 7 patients with stage T2 and 4 patients with stage T3 were included in this study. Four different 3D treatment plans (rotation, 4-field, 5-field and 6-field technique) were calculated for each patient. Dose was calculated with the reference point at the isocenter (100%). The planning target volume was encompassed within the 95% isodose surface. All the techniques used different shaped portal for each beam. Dose volume histograms were created and compared for the planning target volume and the organs at risk (33%, 50%, 66% volume level) in all techniques.ResultsThe 4 different three-dimensional planning techniques revealed no differences concerning dose homogeneity within the planning target volume. The dose volume distribution at organs at risk show differences between the calculated techniques. In our study the best protection for bladder and rectum in stage T1 and T2 was achieved by the 6-field technique. A significant difference was achieved between 6-field and 4-field technique only in the 50% volume of the bladder (p = 0.034), between the 6-field and rotation technique (all volume levels) and between 5-field and rotation technique (all volume levels). In stage T1, T2 6-field and 4-field technique in 50% (p = 0.033) and 66% (p = 0.011) of the rectum volume. In stage T3 a significant difference was not observed between the 4 techniques. The best protection of head of the femur was achieved by the rotation technique.ConclusionIn the localized radiotherapy of prostate cancer in stage T1 or T2 the best protection for bladder and rectum was achieved by a 3D-planned conformai 6-field technique. If the seminal vesicles have been included in the target volume and in the case of large planning target volume other techniques should be taken for a better protection for organs at risk e. g. a 3D-planned 4-field technique box technique.PURPOSE Four different three-dimensional planning techniques for localized radiotherapy of prostate cancer were compared with regard to dose homogeneity within the target volume and dose to organs at risk, dependent upon tumor stage. PATIENTS AND METHODS Six patients with stage T1, 7 patients with stage T2 and 4 patients with stage T3 were included in this study. Four different 3D treatment plans (rotation, 4-field, 5-field and 6-field technique) were calculated for each patient. Dose was calculated with the reference point at the isocenter (100%). The planning target volume was encompassed within the 95% isodose surface. All the techniques used different shaped portal for each beam. Dose volume histograms were created and compared for the planning target volume and the organs at risk (33%, 50%, 66% volume level) in all techniques. RESULTS The 4 different three-dimensional planning techniques revealed no differences concerning dose homogeneity within the planning target volume. The dose volume distribution at organs at risk show differences between the calculated techniques. In our study the best protection for bladder and rectum in stage T1 and T2 was achieved by the 6-field technique. A significant difference was achieved between 6-field and 4-field technique only in the 50% volume of the bladder (p = 0.034), between the 6-field and rotation technique (all volume levels) and between 5-field and rotation technique (all volume levels). In stage T1, T2 6-field and 4-field technique in 50% (p = 0.033) and 66% (p = 0.011) of the rectum volume. In stage T3 a significant difference was not observed between the 4 techniques. The best protection of head of the femur was achieved by the rotation technique. CONCLUSION In the localized radiotherapy of prostate cancer in stage T1 or T2 the best protection for bladder and rectum was achieved by a 3D-planned conformal 6-field technique. If the seminal vesicles have been included in the target volume and in the case of large planning target volume other techniques should be taken for a better protection for organs at risk e. g. a 3D-planned 4-field technique box technique.

Current standards and future directions for prostate cancer radiation therapy

Definitive radiation therapy is a well-recognized curative treatment option for localized prostate cancer. A suitable technique, dose, target volume and the option of a combination with androgen deprivation therapy need to be considered. An optimal standard external beam radiotherapy currently includes intensity-modulated and image-guided radiotherapy techniques with total doses of ≥76–78 Gy in conventional fractionation. Protons or carbon ions are alternatives available only in specific centers. Data from several randomized studies increasingly support the rationale for hypofractionated radiotherapy. A simultaneous integrated boost with dose escalation focused on a computed tomography/PET- or MRI/magnetic resonance spectroscopy-detected malignant lesion is one option to increase tumor control, with potentially no additional toxicity. The application of a spacer is a promising concept for optimal protection of the rectal wall.