Matthias Guckenberger

Stereotactic radiotherapy of primary liver cancer and hepatic metastases

The purpose was to evaluate the clinical results of stereotactic radiotherapy in primary liver tumors and hepatic metastases. Five patients with primary liver cancer and 39 patients with 51 hepatic metastases were treated by stereotactic radiotherapy since 1997. Twenty-eight targets were treated in a “low-dose”-group with 3×10 Gy (n = 27) or 4×7 Gy (n = 1) prescribed to the PTV-encl. 65%-isodose. In a “high-dose”-group patients were treated with 3×12 − 12.5 Gy (n = 19; same dose prescription) or 1×26 Gy/PTV-enclosing 80%-isodose (n = 9). Median follow-up was 15 months (2–48 months) for primary liver cancer and 15 months (2–85 months) for hepatic metastases. While all primary liver cancers were controlled, nine local failures (3–19 months) of 51 metastases were observed resulting in an actuarial local control rate of 92% after 12 months and 66% after 24 months and later. A borderline significant correlation between dose and local control was observed (p = 0.077): the actuarial local control rate after 12 and 24 months was 86% and 58% in the low-dose-group versus 100% and 82% in the high-dose-group. In multivariate analysis high versus low-dose was the only significant factor predicting local control (p = 0.0089). Overall survival after 1 and 2 years was 72% and 32% for all patients and was impaired due to systemic progression of disease. No severe acute or late toxicity exceeding RTOG/EORTC-score 2 were observed. Stereotactic irradiation of primary liver cancer and hepatic metastases offers a locally effective treatment without significant complications in patients, who are not amenable for surgery. Patient selection is important, because those with low risk for systemic progression are more likely to benefit from this approach.

Is a single arc sufficient in volumetric-modulated arc therapy (VMAT) for complex-shaped target volumes?

PURPOSE To compare step-and-shoot intensity-modulated radiotherapy (ss-IMRT) with volumetric-modulated arc therapy (VMAT) for complex-shaped target volumes with a simultaneous integrated boost (SIB). MATERIALS AND METHODS This retrospective planning study was based on 20 patients composed of prostate cancer (n=5), postoperative (n=5) or primary (n=5) radiotherapy for pharyngeal cancer and for cancer of the paranasal sinuses (n=5); a SIB with two or three dose levels was planned in all patients. For each patient, one ss-IMRT plan with direct-machine-parameter optimization (DMPO) and VMAT plans with one to three arcs (SmartArc technique) were generated in the Pinnacle planning system. RESULTS Single arc VMAT improved target coverage and dose homogeneity in radiotherapy for prostate cancer. Two and three VMAT arcs were required to achieve equivalent results compared to ss-IMRT in postoperative and primary radiotherapy for pharyngeal cancer, respectively. In radiotherapy for cancer of the paranasal sinuses, multiarc VMAT resulted in increased spread of low doses to the lenses and decreased target coverage in the region between the orbits. CONCLUSIONS The complexity of the target volume determined whether single arc VMAT was equivalent to ss-IMRT. Multiple arc VMAT improved results compared to single arc VMAT at cost of increased delivery times, increased monitor unites and increased spread of low doses.

Precision of image-guided radiotherapy (IGRT) in six degrees of freedom and limitations in clinical practice.

Purpose:To evaluate the precision of image-guided radiotherapy (IGRT) using cone-beam computed tomography (CB-CT) for volume imaging and a robotic couch for correcting setup errors in six degrees of freedom.Patients and Methods:47 consecutive patients with 372 fractions were classified according to whether a patient fixation device was used (patfix: n = 28) or not (patnon-fix: n = 19). Prior to treatment a CB-CT was acquired and translational and rotational setup errors were corrected online without an action level using a robotic couch (HexaPOD). A second CB-CT was acquired after the correction process and after treatment in 134 and 238 fractions, respectively.Results:In 17 fractions (4.6%) rotational errors > 3° exceeded the motion range of the HexaPOD. Errors (3D vector) after the correction process were significantly smaller for patfix compared to patnon-fix (p < 0.001): 0.9 mm ± 0.5 mm and 1.6 mm ± 0.8 mm, respectively. For patnon-fix the correction of rotational errors resulted in displacements of the patients on the angled couch of 0.6 mm/1°. Intrafractional motion further decreased precision in patnon-fix but not in patfix.Conclusion:Very high precision in cranial and extracranial treatment of immobilized patients was demonstrated. Without application of adequate immobilization the correction of rotational errors and intrafractional patient motion significantly decreased the accuracy of the online correction protocol.Ziel:Untersucht wurde die Präzision eines bildgestützten Bestrahlungsprotokolls, basierend auf Volumenbildgebung mittels Cone-Beam-Computertomographie (CB-CT) und Korrektur von Lagerungsfehlern in sechs Freiheitsgraden.Patienten und Methodik:47 Patienten mit 372 Behandlungsfraktionen wurden ausgewertet: Differenziert wurde zwischen Patienten, die auf dem Behandlungstisch fixiert wurden (patfix: n = 28) oder nicht (patnon-fix: n = 19). Vor der Behandlung wurde ein CB-CT angefertigt, und translatorische und rotatorische Lagerungsfehler wurden vollständig mittels eines robotischen Behandlungstisches (HexaPOD) korrigiert. Bildgebung nach der Fehlerkorrektur und nach der Behandlung wurde in jeweils 134 und 238 Fraktionen durchgeführt.Ergebnisse:Bei 17 Fraktionen (4,6%) überschritten die Rotationsfehler die Reichweite des HexaPOD von 3°. Fehler nach der Korrektur (3D-Vektor) waren bei patnon-fix im Vergleich zu patfix signifikant größer (p < 0,001): 1,6 mm ± 0,8 mm versus 0,9 mm ± 0,5 mm. Bei patnon-fix führte die Korrektur von Rotationsfehlern zu einer Verlagerung der Patienten auf dem abgewinkelten HexaPOD von 0,6 mm/1°. Intrafraktionelle Patientenbewegung resultierte in weiteren Fehlern bei patnon-fix, jedoch nicht bei patfix.Schlussfolgerung:Bei Immobilisierung der Patienten wurde eine Präzision mittels bildgestützter Radiotherapie von 1 mm und 1° erreicht. Ohne ausreichende Immobilisation reduzieren Verlagerungen nach Korrektur von Rotationsfehlern und intrafraktionelle Patientenbewegungen den Nutzen eines solches Behandlungsprotokolls erheblich.

A Collaborative Analysis of Stereotactic Lung Radiotherapy Outcomes for Early-Stage Non–Small-Cell Lung Cancer Using Daily Online Cone-Beam Computed Tomography Image-Guided Radiotherapy

Introduction: We report lung stereotactic-body radiotherapy (SBRT) outcomes for a large pooled cohort treated using daily online cone-beam computed tomography. Methods: Five hundred and five stage I–IIB (T1-3N0M0) non–small-cell lung cancer (NSCLC) cases underwent SBRT using cone-beam computed tomography image guidance at five international institutions from 1998 to 2010. Median age was 74 years (range, 42–92) whereas median forced expiratory volume in 1 second/diffusing lung capacity for carbon monoxide were 1.4 liter (65%) and 10.8 ml/min/mmHg (53%). Of the 505 cases, 64% were biopsy proven and 87% medically inoperable. Staging was: IA 63%, IB 33%, IIA 2%, and recurrent 1%. Median max tumor dimension was 2.6 cm (range, 0.9–8.5). Median heterogeneously calculated volumetric prescription dose (PD) was 54 Gy (range, 20–64 Gy) in three fractions (range, 1–15) over 8 days (range, 1–27). Median biologically equivalent PD biological equivalent doses (BED10) was 132 Gy (range, 60–180). Results: With a median follow-up of 1.6 years (range, 0.1–7.3), the 2-year Kaplan–Meier local control (LC), regional control, and distant metastasis (DM) rates were 94%, 89%, and 20%, respectively, whereas cause-specific and overall survival were 87% and 60% (78% operable, 58% inoperable, p = 0.01), respectively. Stage, gross-tumor volume size (≥ 2.7 cm) and PD(BED10) predicted local relapse (LR) and DM. LR was 15% for BED10 less than 105 Gy versus 4% for BED10 of 105 Gy or more (p < 0.001); DM was 31% versus 18% for BED10 less than 105 versus 105 Gy or more (p = 0.01). On multivariate analysis, PD(BED10) and elapsed days during radiotherapy predicted LR; gross-tumor volume size predicted DM. Grade 2 or higher pneumonitis, rib fracture, myositis, and dermatitis were 7%, 3%, 1%, and 2%, respectively. Conclusions: In the largest early-stage NSCLC SBRT data set to date, a high rate of local control was achieved, which was correlated with a PD(BED10) of 105 Gy or more. Failures were primarily distant, severe toxicities were rare, and overall survival was encouraging in operable patients.

Cone-beam CT based image-guidance for extracranial stereotactic radiotherapy of intrapulmonary tumors

Cone-beam CT (CB-CT) based image-guidance was evaluated for extracranial stereotactic radiotherapy of intrapulmonary tumors. A total of 21 patients (25 lesions: prim. NSCLC n = 6; pulmonary metastases n = 19) were treated with stereotactic radiotherapy (1 to 8 fractions). Prior to every fraction a CB-CT was acquired in treatment position, errors between planned and actual tumor position were measured and corrected. Intra- and inter-observer variability of manual evaluation of tumor position error was investigated and this manual method was compared with automatic image registration. Based on CB-CTs from 66 fractions the discrepancy (3-D vector) between planned and actual tumor position was 7.7 mm ±1.3 mm. Tumor position error relative to the bony anatomy was 5.3 mm ±1.2 mm, the correlation between bony anatomy and tumor position was poor. Intra-observer and inter-observer variability of manual evaluation of tumor position error was 0.9 mm ±0.8 mm and 2.3 mm ±1.1 mm, respectively. Automatic image registration showed highly reproducible results (<1 mm). However, compared with manual registration a systematic error was found in direction of predominant tumor breathing motion (2.5 mm vs 1.4 mm). Image-guidance using CB-CT was validated for high precision radiotherapy of intrapulmonary tumors. It was shown that both the planning reference and the verification image study have to consider tumor breathing motion.

Radiotherapy in adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare malignancy, and patients with ACC have a poor prognosis. Even after radical surgery, up to 85% of patients develop recurrent disease. Systemic treatment options still have limited efficacy. Because the role of radiotherapy is not defined well and because ACC often is considered radioresistant, the authors reviewed the available data on radiotherapy for ACC. Original articles and reviews were identified using a PubMed search strategy that included the period up to July 2008. Ten articles were identified that covered radiotherapy in a total of 129 patients with ACC (64 patients received postoperative irradiation, and 65 patients received palliative therapy for advanced disease). In addition, 26 patients were identified in the German ACC Registry who received palliative radiotherapy. Furthermore, patterns of failure after adjuvant radiotherapy were investigated, and the authors provided recommendations for patient selection, treatment planning, and treatment protocols. In an adjuvant setting, postoperative radiotherapy was able to prevent local recurrence in the majority of patients. In those with advanced disease, a response to radiotherapy was observed in 57% of patients who received palliative radiotherapy. Therefore, the authors concluded that radiotherapy may play an important role in the care of patients with ACC. Until better evidence is available, the authors recommended the following approach: Adjuvant radiotherapy to the tumor bed should be considered in patients at high risk for local recurrence (eg, incomplete/R1 resection); a total dose of >40 grays (Gy) with single fractions of 1.8 Gy to 2 Gy should be administered (including a boost volume to reach from 50 Gy to 60 Gy in individual patients); and radiotherapy in a palliative setting may be used for symptomatic metastases to bone, brain, or vena cava obstruction. With state‐of‐the‐art technology, acute and long‐term toxicities mostly were mild to moderate. However, the authors concluded that prospective investigations would be required to fully define the therapeutic potential of this important treatment option. Cancer 2009.

Dose–response relationship for radiation-induced pneumonitis after pulmonary stereotactic body radiotherapy

PURPOSE To evaluate dosimetric factors predictive for radiation-induced pneumonitis (RP) after pulmonary stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS A retrospective analysis was performed based on 59 consecutive patients treated with cone-beam CT-based image-guided SBRT for primary NSCLC (n=21) or pulmonary metastases (n=54). The majority of patients were treated with radiosurgery of 26 Gy to 80% (n=29) or three fractions of 12.5 Gy to 65% (n=40). To correct for different single fraction doses, local doses were converted to 2 Gy equivalent normalized total doses (NTDs) using α/β ratio of 3 Gy for RP. Dose-volume parameters and incidences of RP ≥ grade II SWOG were fitted using NTCP models. RESULTS Eleven patients developed RP grade II. With an average MLD of 10.3±5.6 Gy to the ipsilateral lung, a significant dose-response relationship was observed: the MLD was 12.5±4.3 Gy and 9.9±5.8 Gy for patients with and without development of RP, respectively. Additionally, volumes of the lung exposed to minimum doses between 2.5 and 50 Gy (V(2.5)-V(50)) were correlated with incidences of RP with a continuous decrease of the goodness of fit for higher doses. CONCLUSIONS The MLD and V(2.5)-V(50) of the ipsilateral lung were correlated with incidences of RP after pulmonary SBRT.

Transcriptome Analysis of Neisseria meningitidis during Infection

Neisseria meningitidis is the cause of septicemia and meningococcal meningitis. During the course of infection, N. meningitidis encounters multiple environments within its host, which makes rapid adaptation to environmental changes a crucial factor for neisserial pathogenicity. Employing oligonucleotide-based DNA microarrays, we analyzed the transcriptome of N. meningitidis during two key steps of meningococcal infection, i.e., the interaction with epithelial cells (HeLa cells) and endothelial cells (human brain microvascular endothelial cells). Seventy-two genes were differentially regulated after contact with epithelial cells, and 48 genes were differentially regulated after contact with endothelial cells, including a considerable proportion of well-known virulence genes. While a considerable number of genes were in concordance between bacteria adherent to both cell types, we identified several open reading frames that were differentially regulated in only one system. The data obtained with this novel approach may provide insight into the pathogenicity mechanisms of N. meningitidis and could demonstrate the importance of gene regulation on the transcriptional level during different stages of meningococcal infection.

Intensity-Modulated Radiotherapy (IMRT) of Localized Prostate Cancer

Purpose:The present status of intensity-modulated radiation therapy (IMRT) for treatment of localized prostate cancer is discussed.Methods:The technological basis of IMRT and the rationale for the use in treatment of prostate cancer are described. Clinical results from the literature are presented and treatment strategies for further reduction of safety margins are outlined.Results and Discussion:Multiple planning studies demonstrated the dosimetric advantage of IMRT compared to three-dimensional conformal radiotherapy. Though randomized studies are missing, retrospective studies indicate that improved dose distributions of IMRT transfer into improved rates of local control and/or lower rates of rectal toxicity. However, with standard safety margins the benefit of IMRT seems to be limited. Image guidance is considered to be essential to reduce errors of patient setup and internal motion of the prostate.Ziel:Diskutiert wird der aktuelle Stand der intensitätsmodulierten Strahlentherapie (IMRT) in der Behandlung des lokal begrenzten Prostatakarzinoms.Methodik:Die technischen Grundlagen der IMRT werden umrissen, und die Rationale für den Einsatz in der Behandlung des Prostatakarzinoms wird beschrieben. Erste klinische Resultate aus der Literatur werden präsentiert und zukünftige Strategien zur Verkleinerung von Sicherheitssäumen aufgezeigt.Ergebnisse und DiskussionDer Vorteil der IMRT zur Modellierung hochkonformaler Dosisverteilungen wurde in zahlreichen Planungsstudien gezeigt. Trotz des Fehlens randomisierter Studien weisen retrospektive Daten darauf hin, dass mittels IMRT im Vergleich zur dreidimensionalen konformalen Bestrahlungstechnik die lokale Kontrolle verbessert und/oder die rektale Toxizität reduziert werden können. Dennoch erscheint der Nutzen der IMRT bei der Verwendung von Standardsicherheitssäumen limitiert. Bildgestützte Strahlentherapie wird daher als essentiell angesehen, um Lagerungsfehler der Patienten und interne Bewegungen der Prostata zu kompensieren.

Tumor tracking and motion compensation with an adaptive tumor tracking system (ATTS): System description and prototype testing

A novel system for real-time tumor tracking and motion compensation with a robotic HexaPOD treatment couch is described. The approach is based on continuous tracking of the tumor motion in portal images without implanted fiducial markers, using the therapeutic megavoltage beam, and tracking of abdominal breathing motion with optical markers. Based on the two independently acquired data sets the table movements for motion compensation are calculated. The principle of operation of the entire prototype system is detailed first. In the second part the performance of the HexaPOD couch was investigated with a robotic four-dimensional-phantom capable of simulating real patient tumor trajectories in three-dimensional space. The performance and limitations of the HexaPOD table and the control system were characterized in terms of its dynamic behavior. The maximum speed and acceleration of the HexaPOD were 8mm∕s and 34.5mm∕s2 in the lateral direction, and 9.5mm∕s and 29.5mm∕s2 in longitudinal and anterior-posterior direction, respectively. Base line drifts of the mean tumor position of realistic lung tumor trajectories could be fully compensated. For continuous tumor tracking and motion compensation a reduction of tumor motion up to 68% of the original amplitude was achieved. In conclusion, this study demonstrated that it is technically feasible to compensate breathing induced tumor motion in the lung with the adaptive tumor tracking system.