Franz Zehentmayr

A strategy for the use of image-guided radiotherapy (IGRT) on linear accelerators and its impact on treatment margins for prostate cancer patients.

Background and PurposeIn external beam radiotherapy of prostate cancer, the consideration of various systematic error types leads to wide treatment margins compromising normal tissue tolerance. We investigated if systematic set-up errors can be reduced by a set of initial image-guided radiotherapy (IGRT) sessions.Patients and Methods27 patients received daily IGRT resulting in a set of 882 cone-beam computed tomographies (CBCTs). After matching to bony structures, we analyzed the dimensions of remaining systematic errors from zero up to six initial IGRT sessions and aimed at a restriction of daily IGRT for 10% of all patients. For threshold definition, we determined the standard deviations (SD) of the shift corrections and selected patients out of this range for daily image guidance. To calculate total treatment margins, we demanded for a cumulative clinical target volume (CTV) coverage of at least 95% of the specified dose in 90% of all patients.ResultsThe gain of accuracy was largest during the first three IGRTs. In order to match precision and workload criteria, thresholds for the SD of the corrections of 3.5 mm, 2.0 mm and 4.5 mm in the left-right (L-R), cranial-caudal (C-C), and anterior-posterior (A-P) direction, respectively, were identified. Including all other error types, the total margins added to the CTV amounted to 8.6 mm in L-R, 10.4 mm in C-C, and 14.4 mm in A-P direction.ConclusionOnly initially performed IGRT might be helpful for eliminating gross systematic errors especially after virtual simulation. However, even with daily IGRT performance, a substantial PTV margin reduction is only achievable by matching internal markers instead of bony anatomical structures.ZusammenfassungHintergrundBei der Teletherapie des Prostatakarzinoms führt die Berücksichtigung verschiedener systematischer Fehler zu großen Sicherheitsrändern auf Kosten der Normalgewebetoleranz. Wir untersuchten, inwieweit systematische Lagerungsfehler durch initiale bildgeführte Radiotherapie (IGRT) reduziert werden können.Patienten und MethodikEs wurden 882 Cone-Beam-Comutertomographien (CBCT) von insgesamt 27 Patienten analysiert. Nach der Korrektur auf knöcherne Strukturen wurde das Ausmaß des Lagerungsfehlers als gemittelter Wert der Verschiebungen nach null bis sechs CBCTs untersucht. Aus den Standardabweichungen (SD) der Verschiebungen wurden Schwellwerte für maximal 10% aller Patienten definiert, die tägliche Bildführung erhalten sollten. Für die Berechnung der Sicherheitsränder für das Planzielvolumen (PTV) forderten wir eine mindestens 95%ige kumulative Dosisabdeckung des klinischen Zielvolumens bei 90% der Patienten.ErgebnisseDrei CBCT stellten den optimalen Kompromiss zwischen Arbeitsbelastung und erzielbarer Genauigkeit durch initiale Bildführung dar (Tabelle 1). Die Schwellwerte für die SD, ab denen wir tägliche IGRT forderten, betrugen 3,5 mm in Links-rechts-(L-R-), 2,0 mm in kranial-kaudaler (C-C-) und 4,5 mm in anterior-posteriorer (A-P-)Richtung (Abbildung 1). Unter Berücksichtigung aller anderen Fehlertypen (Tabelle 2) wurden für das PTV kumulative Sicherheitsränder von L-R 8,6 mm, C-C 10,4 mm und A-P 14,4 mm ermittelt (Tabelle 3, Abbildung 2).SchlussfolgerungAusschließlich initial durchgeführte Bildführung mag zwar größere systematische Fehler, speziell nach virtueller Simulation, kompensieren, eine deutliche Reduktion der PTV-Sicherheitsränder ist aber selbst bei täglicher IGRT nur durch Abgleich auf interne Marker anstelle von knöchernen Strukturen möglich.

Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases

BackgroundRecently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information.MethodsFrom 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months.ResultsAt 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival.ConclusionsModerate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information.

Curative treatment of oesophageal carcinoma: current options and future developments.

Since the 1980s major advances in surgery, radiotherapy and chemotherapy have established multimodal approaches as curative treatment options for oesophageal cancer. In addition the introduction of functional imaging modalities such as PET-CT created new opportunities for a more adequate patient selection and therapy response assessment.The majority of oesophageal carcinomas are represented by two histologies: squamous cell carcinoma and adenocarcinoma. In recent years an epidemiological shift towards the latter was observed. From a surgical point of view, adenocarcinomas, which are usually located in the distal third of the oesophagus, may be treated with a transhiatal resection, whereas squamous cell carcinomas, which are typically found in the middle and the upper third, require a transthoracic approach. Since overall survival after surgery alone is poor, multimodality approaches have been developed. At least for patients with locally advanced tumors, surgery alone can no longer be advocated as routine treatment. Nowadays, scientific interest is focused on tumor response to induction radiochemotherapy. A neoadjuvant approach includes the early and accurate assessment of clinical response, optimally performed by repeated PET-CT imaging and endoscopic ultrasound, which may permit early adaption of the therapeutic concept. Patients with SCC that show clinical response by PET CT are considered to have a better prognosis, regardless of whether surgery will be performed or not. In non-responding patients salvage surgery improves survival, especially if complete resection is achieved.

“Augmented Reality” in Conventional Simulation by Projection of 3-D Structures into 2-D Images

Background and Purpose:In this study, a new method is introduced, which allows the overlay of three-dimensional structures, that have been delineated on transverse slices, onto the fluoroscopy from conventional simulators in real time.Patients and Methods:Setup deviations between volumetric imaging and simulation were visualized, measured and corrected for 701 patient isocenters.Results:Comparing the accuracy to mere virtual simulation lacking additional X-ray imaging, a clear benefit of the new method could be shown. On average, virtual prostate simulations had to be corrected by 0.48 cm (standard deviation [SD] 0.38), and those of the breast by 0.67 cm (SD 0.66).Conclusion:The presented method provides an easy way to determine entity-specific safety margins related to patient setup errors upon registration of bony anatomy (prostate 0.9 cm for 90% of cases, breast 1.3 cm). The important role of planar X-ray imaging was clearly demonstrated. The innovation can also be applied to adaptive image-guided radiotherapy (IGRT) protocols.Hintergrund und Ziel:Es wird ein Verfahren vorgestellt, das die Einblendung von dreidimensionalen Strukturen, die zuvor z.B. auf axialen Schnittbildern segmentiert wurden, in Durchleuchtungsaufnahmen am konventionellen Simulator in Echtzeit erlaubt.Patienten und Methodik:Mit dieser Technologie wurden an 701 Patientenisozentren Lagerungsunterschiede zwischen der Schnittbildgebung und der Simulation visualisiert, vermessen und korrigiert.Ergebnisse:Im Vergleich der Genauigkeit mit der rein virtuellen Simulation, bei der auf Röntgenbildgebung verzichtet wird, zeigte sich eine deutliche Überlegenheit der neuen Methode. Im Mittel wurden virtuell simulierte Prostatabestrahlungen um 0,48 cm (Standardabweichung [SD] 0,38) und jene der Mamma um 0,67 cm (SD 0,66) korrigiert.Schlussfolgerung:Das vorgestellte Verfahren erlaubt die einfache Bestimmung entitätsspezifischer Sicherheitsränder für Lagerungsungenauigkeiten von knöchernen Strukturen (Prostatabestrahlung 0,9 cm für 90% der Fälle, Mamma 1,3 cm; Tabelle 2). Die Bedeutung von planarer kV-Bildgebung konnte gezeigt werden. Das innovative Verfahren ist auch im Rahmen von Protokollen zur adaptiven, bildgeführten Radiotherapie (IGRT) einsetzbar.

Augmented reality in conventional simulation by projection of 3-D structures into 2-D images: a comparison with virtual methods.

Background and Purpose:In this study, a new method is introduced, which allows the overlay of three-dimensional structures, that have been delineated on transverse slices, onto the fluoroscopy from conventional simulators in real time.Patients and Methods:Setup deviations between volumetric imaging and simulation were visualized, measured and corrected for 701 patient isocenters.Results:Comparing the accuracy to mere virtual simulation lacking additional X-ray imaging, a clear benefit of the new method could be shown. On average, virtual prostate simulations had to be corrected by 0.48 cm (standard deviation [SD] 0.38), and those of the breast by 0.67 cm (SD 0.66).Conclusion:The presented method provides an easy way to determine entity-specific safety margins related to patient setup errors upon registration of bony anatomy (prostate 0.9 cm for 90% of cases, breast 1.3 cm). The important role of planar X-ray imaging was clearly demonstrated. The innovation can also be applied to adaptive image-guided radiotherapy (IGRT) protocols.Hintergrund und Ziel:Es wird ein Verfahren vorgestellt, das die Einblendung von dreidimensionalen Strukturen, die zuvor z.B. auf axialen Schnittbildern segmentiert wurden, in Durchleuchtungsaufnahmen am konventionellen Simulator in Echtzeit erlaubt.Patienten und Methodik:Mit dieser Technologie wurden an 701 Patientenisozentren Lagerungsunterschiede zwischen der Schnittbildgebung und der Simulation visualisiert, vermessen und korrigiert.Ergebnisse:Im Vergleich der Genauigkeit mit der rein virtuellen Simulation, bei der auf Röntgenbildgebung verzichtet wird, zeigte sich eine deutliche Überlegenheit der neuen Methode. Im Mittel wurden virtuell simulierte Prostatabestrahlungen um 0,48 cm (Standardabweichung [SD] 0,38) und jene der Mamma um 0,67 cm (SD 0,66) korrigiert.Schlussfolgerung:Das vorgestellte Verfahren erlaubt die einfache Bestimmung entitätsspezifischer Sicherheitsränder für Lagerungsungenauigkeiten von knöchernen Strukturen (Prostatabestrahlung 0,9 cm für 90% der Fälle, Mamma 1,3 cm; Tabelle 2). Die Bedeutung von planarer kV-Bildgebung konnte gezeigt werden. Das innovative Verfahren ist auch im Rahmen von Protokollen zur adaptiven, bildgeführten Radiotherapie (IGRT) einsetzbar.

Long-Term Outcome of Mitomycin C- and 5-FU-Based Primary Radiochemotherapy for Esophageal Cancer

Background and Purpose:For definitive radiochemotherapy, 5-fluorouracil/cisplatin protocols have been considered the standard of care for esophageal carcinoma over the last 2 decades. By contrast, most patients treated at the University Hospital, LMU Munich, Germany, received 5-fluorouracil/mitomycin C. The objective of this retrospective analysis was to determine the value of 5-fluorouracil/mitomycin-C-based therapy.Patients and Methods:Tumor stage, treatment received, and outcome data of patients treated for esophageal cancer between 1982 and 2007 were collected; endpoint of the analysis was overall survival.Results:298 patients with inoperable cancer of the esophagus were identified (16.8% adenocarcinoma, 77.5% squamous cell carcinoma). At diagnosis, 61.7% (184/298) had UICC stage III–IV, 54.4% (162/298) positive lymph nodes, and 26.5% (79/298) metastatic disease. 74.5% of all patients (222/298) received radiation doses between 55 and 65 Gy, 65.8% (196/298) were subjected to concomitant chemotherapy. The median follow-up period (patients alive) was 4.1 years. A significant increase of overall survival (p < 0.0001) in the radiochemotherapy versus the radiotherapy-alone group was observed. 52% (102/196) in the 5-fluorouracil/ mitomycin C group had tumor stages comparable to the RTOG 85-01 study cohort (T1–3 N0–1 M0). The median survival in this subgroup was 18.2 months, 3- and 5-year survival rates were 22.7% (21/102) and 15.0% (13/102), respectively.Conclusion:Despite being nominally inferior to platinum-based radiochemotherapy, the overall survival rates are in a similar range. Thus, the mitomycin-C-based radiochemotherapy approach may considered to be as effective as the standard therapy. However, there is no randomized trial available in order to prove the equality.Hintergrund und Ziel:Radiochemotherapie mit 5-Fluorouracil und Cisplatin gilt seit 2 Jahrzehnten als Standard fur die primare Behandlung des Osophaguskarzinoms. Im Gegensatz dazu erhielten die meisten Patienten, die im Klinikum der LMU Munchen behandelt wurden, eine definitive Radiochemotherapie mit 5-Fluorouracil und Mitomycin C. Retrospektiv wurde gepruft, zu welchen Ergebnissen das angewandte Regime im Vergleich zur Standardtherapie fuhrte.Patienten und Methodik:Retrospektiv wurden Tumorstadium, Therapieform und das Outcome der Patienten mit Osophaguskarzinom, die zwischen 1982 und 2007 behandelt wurden, erhoben (Tabelle 1). Primarer Endpunkt war das Gesamtuberleben (Abbildungen 1a bis 1c).Ergebnisse:298 Patienten (16,8% Adenokarzinome [50/298], 77,5% Plattenepithelkarzinome [231/298]) wurden primar behandelt. Bei Diagnosestellung wiesen 61,7% (184/298) UICC-Stadien III–IV, 54,4% (162/298) einen positiven Lymphknotenstatus sowie 26,5% (79/298) Fernmetastasen auf. 74,5% aller Patienten (222/298) erhielten eine Bestrahlungsdosis zwischen 55 und 65 Gy. 65,8% (196/298) bekamen parallel dazu eine Chemotherapie. Der mediane Nachbeobachtungszeitraum betrug 4,1 Jahre. Es zeigte sich ein signifikant langeres Uberleben in der Radiochemotherapiegruppe im Vergleich zur Radiotherapiegruppe (p < 0,0001). 102/196 Patienten (52%) in der Radiochemotherapiegruppe hatten Tumorstadium T1–3 N0–1 M0, entsprechend der RTOG-85-01-Kohorte. In dieser Subgruppe zeigten sich ein medianes Uberleben von 18,2 Monaten und Uberlebensraten von 22,7% (21/102) bzw. 15,0% (13/102) nach 3 respektive 5 Jahren (Tabellen 2 und 4).Schlussfolgerung:Obwohl in diesem unselektionierten Kollektiv der Standardtherapie mit Cisplatin/5-Fluorouracil nominell unterlegen, sind die Uberlebensraten in einem vergleichbaren Bereich (Tabelle 3). Eine Radiochemotherapie mit 5-Fluorouracil und Mitomycin C scheint ahnlich effektiv wie die Standardtherapie zu sein. Allerdings gibt es keine randomisierte Studie, um dies zu beweisen.

Boost IORT in Breast Cancer: Body of Evidence

The term IORT (intraoperative radiotherapy) is currently used for various techniques that show decisive differences in dose delivery. The largest evidence for boost IORT preceding whole breast irradiation (WBI) originates from intraoperative electron treatments with single doses around 10 Gy, providing outstandingly low local recurrence rates in any risk constellation also at long term analyses. Compared to other boost methods, an intraoperative treatment has evident advantages as follows. Precision. Direct visualisation of the tumour bed during surgery guarantees an accurate dose delivery. This fact has additionally gained importance in times of primary reconstruction techniques after lumpectomy to optimise cosmetic outcome. IORT is performed before breast tissue is mobilised for plastic purposes. Cosmesis. As a consequence of direct tissue exposure without distension by hematoma/seroma, IORT allows for small treatment volumes and complete skin sparing, both having a positive effect on late tissue tolerance and, hence, cosmetic appearance. Patient Comfort. Boost IORT marginally prolongs the surgical procedure, while significantly shortening postoperative radiotherapy. Its combination with a 3-week hypofractionated external beam radiotherapy to the whole breast (WBI) is presently tested in the HIOB trial (hypofractionated WBI preceded by IORT electron boost), a prospective multicenter trial of the International Society of Intraoperative Radiotherapy (ISIORT).

miR-16-5p Is a Stably-Expressed Housekeeping MicroRNA in Breast Cancer Tissues from Primary Tumors and from Metastatic Sites

For quantitative microRNA analyses in formalin-fixed paraffin-embedded (FFPE) tissue, expression levels have to be normalized to endogenous controls. To investigate the most stably-expressed microRNAs in breast cancer and its surrounding tissue, we used tumor samples from primary tumors and from metastatic sites. MiRNA profiling using TaqMan® Array Human MicroRNA Cards, enabling quantification of 754 unique human miRNAs, was performed in FFPE specimens from 58 patients with metastatic breast cancer. Forty-two (72%) samples were collected from primary tumors and 16 (28%) from metastases. In a cross-platform analysis of a validation cohort of 32 FFPE samples from patients with early breast cancer genome-wide microRNA expression analysis using SurePrintG3 miRNA (8 × 60 K)® microarrays from Agilent® was performed. Eleven microRNAs could be detected in all samples analyzed. Based on NormFinder and geNorm stability values and the high correlation (rho ≥ 0.8) with the median of all measured microRNAs, miR-16-5p, miR-29a-3p, miR-126-3p, and miR-222-3p are suitable single gene housekeeper candidates. In the cross-platform validation, 29 human microRNAs were strongly expressed (mean log2-intensity > 10) and 21 of these microRNAs including miR-16-5p and miR-29a-3p were also stably expressed (CV < 5%). Thus, miR-16-5p and miR-29a-3p are both strong housekeeper candidates. Their Normfinder stability values calculated across the primary tumor and metastases subgroup indicate that miR-29a-3p can be considered as the strongest housekeeper in a cohort with mainly samples from primary tumors, whereas miR-16-5p might perform better in a metastatic sample enriched cohort.

Treatment strategies for oesophageal cancer - time-trends and long term outcome data from a large tertiary referral centre

Background and objectivesTreatment options for oesophageal cancer have changed considerably over the last decades with the introduction of multimodal treatment concepts dominating the progress in the field. However, it remains unclear in how far the documented scientific progress influenced and changed the daily routine practice. Since most patients with oesophageal cancer generally suffer from reduced overall health conditions it is uncertain how high the proportion of aggressive treatments is and whether outcomes are improved substantially. In order to gain insight into this we performed a retrospective analysis of patients treated at a larger tertiary referral centre over time course of 25 years.Patients and methodsData of all patients diagnosed with squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the oesophagus, treated between 1983 and 2007 in the department of radiation oncology of the LMU, were obtained. The primary endpoint of the data collection was overall survival (calculated from the date of diagnosis until death or last follow up). Changes in basic clinical characteristics, treatment approach and the effect on survival were analysed after dividing the cohort into five subsequent time periods (I-V) with 5 years each. In a second analysis any pattern of change regarding the use of radio(chemo)therapy (R(C)T) with and without surgery was determined.ResultsIn total, 503 patients with SCC (78.5%) and AC (18.9%) of the oesophagus were identified. The average age was 60 years (range 35-91 years). 56.5% of the patients were diagnose with advanced UICC stages III-IV. R(C)T was applied to 353 (70.2%) patients; R(C)T+ surgery was performed in 134 (26.6%) patients, 63.8% of all received chemotherapy (platinum-based 5.8%, 5-fluorouracil (5-FU)12.1%, 42.3% 5-FU and mitomycin C (MMC)). The median follow-up period was 4.3 years. The median overall survival was 21.4 months. Over the time, patients were older, the formal tumour stage was more advanced, the incidence of AC was higher and the intensified treatment had a higher prevalence. However there was only a trend for an improved OS over the years with no difference between RCT with or without surgery (p = 0.09). The use of radiation doses over 54 Gy and the addition of chemotherapy (p = 0.002) were associated with improved OS.ConclusionAlthough more complex treatment protocols were introduced into clinical routine, only a minor progress in OS rates was detectable. Main predictors of outcome in this cohort was the addition of chemotherapy. The addition of surgery to radio-chemotherapy may only be of value for very limited patient groups.

IOERT as anticipated tumor bed boost during breast-conserving surgery after neoadjuvant chemotherapy in locally advanced breast cancer--results of a case series after 5-year follow-up.

To evaluate retrospectively rates of local (LCR) and locoregional tumor control (LRCR) in patients with locally advanced breast cancer (LABC) who were treated with preoperative chemotherapy (primary systemic treatment, PST) followed by breast‐conserving surgery (BCS) and either intraoperative radiotherapy with electrons (IOERT) preceding whole‐breast irradiation (WBI) (Group 1) or with WBI followed by an external tumor bed boost (electrons or photons) instead of IOERT (Group 2). From 2002 to 2007, 83 patients with clinical Stage II or III breast cancer were enrolled in Group 1 and 26 in Group 2. All patients received PST followed by BCS and axillary lymph node dissection. IOERT boosts were applied by single doses of 9 Gy (90% reference isodose) versus external boosts of 12 Gy (median dose range, 6–16) in 2 Gy/fraction (ICRU). WBI in both groups was performed up to total doses of 51–57 Gy (1.7–1.8 Gy/fraction). The respective median follow‐up times for Groups 1 and 2 amount 59 months (range, 3–115) and 67.5 months (range, 13–120). Corresponding 6‐year rates for LCR, LRCR, metastasis‐free survival, disease‐specific survival and overall survival were 98.5, 97.2, 84.7, 89.2 and 86.4% for Group 1 and 88.1, 88.1, 74, 92 and 92% for Group 2, respectively, without any statistical significances. IOERT as boost modality during BCS in LABC after PST shows a trend to be superior in terms of LCR and LRCR in comparison with conventional boosts.