Nicole Wiedenmann

Radiotherapy for High-Grade Gliomas Does Altered Fractionation Improve the Outcome?

Background and Purpose:The publication of Radiation Therapy Oncology Group (RTOG) Study 83-02 in 1996 stimulated further investigations of altered fractionation, i. e., application of more than one fraction per day, in high-grade gliomas. This review summarizes the results of trials published between January 1997 and June 2002.Material and Methods:To identify suitable trials, a Medline search was performed by use of the following key words: brain tumors/astrocytoma/glioma/high-grade glioma/malignant glioma/glioblastoma multiforme and accelerated radiotherapy/hyperfractionated radiotherapy/altered fractionation. In addition, the search was extended to reference lists of articles and textbooks. Whenever possible, data were extracted from the original papers on an intention-to-treat basis, i. e., patients with protocol violations were not excluded for the purpose of this analysis. Studies in brain stem gliomas, pediatric patients and studies which achieved acceleration by radiosurgery, stereotactic radiotherapy, or brachytherapy rather than conventional external-beam treatment were not included. An exploratory analysis of 2-year survival was also performed. For this purpose, the 2-year survival rate was extracted from each individual study. The total number of 2-year survivors was then calculated for each treatment strategy and compared by use of the χ2-test.Results:The authors identified 1,414 patients from 21 studies; two of these were randomized phase III studies. In seven studies (658 patients), chemotherapy or radiosensitizers were not administered in addition to radiotherapy. The others provide a very heterogeneous set of data, because a large variety of drugs and administration schedules was used. Seven studies included patients with glioblastoma multiforme only, two were limited to patients with anaplastic gliomas. Dose per fraction was 1.2–1.8 Gy in 17 studies and 1.9–2.65 Gy in four. Overall treatment time was 12–31 days, except for one study. Three out of five studies where three fractions per day were administered, included a 2-week break (split-course studies). None of the studies reported a significant improvement in survival by altered fractionation in comparison to either institutional historical controls or their respective randomized control arm. Doses of 60–70 Gy do not appear to improve survival compared to 50–60 Gy. The current data provide no arguments for use of three instead of two fractions per day. Median survival was 10 months after radiotherapy alone (658 patients) and 11 months after combined treatment (756 patients). Regarding 2-year survival rates, radiotherapy alone resulted in 13%, combined chemoradiation or use of sensitizers in 23% (p < 0.0001). However, prognostic factors such as tumor histology were not equally distributed and favor the combined-treatment group. Evaluation of six studies of conventional radiotherapy alone resulted in data from 571 patients. Their median survival was 10.8 months. Cumulative 2-year survival amounted to 15%. The studies of conventional radiotherapy plus chemotherapy or sensitizers included 1,115 patients with a median survival of 11 months (2-year survival rate 18.5%).Conclusion:Altered fractionation shortens the overall treatment time for adult patients with supratentorial high-grade gliomas. However, there is no significant survival improvement.Hintergrund und Ziel:Die Publikation der RTOG-Studie 83-02 im Jahre 1996 führte zu einem gesteigerten Interesse an der Überprüfung unkonventioneller Fraktionierungsschemata, bei denen mehr als eine Fraktion pro Tag gegeben wird. Dieser Übersichtsartikel fasst die Ergebnisse solcher Behandlungen in Studien, die zwischen Januar 1997 und Juni 2002 publiziert wurden, zusammen.Material und Methodik:Um entsprechende Studien zu identifizieren, erfolgte eine Medline-Suche mit folgenden Schlüsselwörtern: brain tumors/astrocytoma/glioma/high-grade glioma/malignant glioma/glioblastoma multiforme und accelerated radiotherapy/hyperfractionated radiotherapy/altered fractionation. Zusätzlich wurde im Literaturverzeichnis der Artikel und von Lehrbüchern gesucht. Wenn möglich, wurden die Daten aus den Originalarbeiten im Sinne einer Intention-to-treat-Analyse extrahiert, d. h., Patienten mit Protokollverletzungen wurden für diese Auswertung nicht ausgeschlossen. Studien zu Hirnstammgliomen, pädiatrische Serien und Studien, die durch Radiochirurgie, stereotaktische Strahlentherapie oder Brachytherapie anstelle von konventioneller perkutaner Strahlentherapie akzelerierten, wurden nicht eingeschlossen. Im Sinne einer explorativen Analyse wurden zusätzlich die 2-Jahres-Überlebensraten der einzelnen Studien bestimmt. Die Gesamtzahl der 2-Jahres-Überlebenden für die verschiedenen Therapieansätze wurde errechnet und mittels χ2-Test verglichen.Ergebnisse:Die Autoren identifizierten 1 414 Patienten in 21 Studien, darunter zwei randomisierte Phase-III-Studien. In sieben Studien (658 Patienten) wurden weder Chemotherapie noch radiosensibilisierende Substanzen zusätzlich zur Bestrahlung verwendet. Die anderen Studien sind sehr heterogen, da eine Vielzahl von Medikamenten und Applikationsschemata benutzt wurde. Sieben Studien schlossen nur Patienten mit Glioblastoma multiforme ein, zwei nur Patienten mit anaplastischen Gliomen. Die Dosis pro Fraktion betrug in 17 Studien 1,2–1,8 Gy und in vier Studien 1,9–2,65 Gy. Die Gesamtbehandlungszeit lag außer in einer Studie bei 12–31 Tagen. Von fünf Studien, in denen drei Fraktionen pro Tag gegeben wurden, wiesen drei eine 2-wöchige Behandlungspause auf („split course“). In keiner der Studien mit eigenem historischen Kontrollarm oder randomisiertem Kontrollarm ergab sich durch eine Modifikation der Fraktionierung ein signifikanter Überlebensvorteil. Dosen zwischen 60 und 70 Gy führten im Vergleich zu 50–60 Gy nicht zu einem verbesserten Überleben. Die vorliegenden Daten liefern keine Argumente für die Applikation von drei Fraktionen pro Tag. Das mediane Überleben betrug 10 Monate nach alleiniger Strahlentherapie (658 Patienten) und 11 Monate nach kombinierter Behandlung (756 Patienten). Die alleinige Bestrahlung führte zu einer 2-Jahres-Überlebensrate von 13%, die kombinierte Radiochemotherapie oder die Gabe sensibilisierender Substanzen zu 23% (p < 0,0001). Allerdings waren die prognostischen Faktoren, wie z.B. Tumorhistologie, nicht gleich verteilt, sondern in den kombiniert behandelten Kollektiven günstiger. Die Auswertung von sechs Studien mit konventionell fraktionierter Strahlentherapie ergab Vergleichsdaten von 571 Patienten. Deren medianes Überleben betrug 10,8 Monate. Die 2-Jahres-Überlebensrate lag bei 15%. Die Studien zur konventionellen Strahlentherapie plus Chemotherapie oder Radiosensibilisierung schlossen 1 115 Patienten ein (medianes Überleben 11 Monate, 2-Jahres-Überlebensrate 18,5%).Schlussfolgerung:Die modifizierte Fraktionierung verkürzt die Gesamtbehandlungszeit erwachsener Patienten mit supratentoriellen hochgradigen Gliomen. Aus dieser Strategie ergibt sich jedoch kein signifikanter Überlebensvorteil.

Whole Brain Irradiation With Hippocampal Sparing and Dose Escalation on Multiple Brain Metastases: A Planning Study on Treatment Concepts

PURPOSE To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). METHODS AND MATERIALS Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individual brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. RESULTS The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55±0.62 Gy and 6.29±0.62 Gy, respectively, when 5-mm and 10-mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8±1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2±0.7 Gy and 32.7±0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23±1.42 Gy in SC. CONCLUSIONS Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery-equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used.

Exploratory geographical analysis of hypoxic subvolumes using 18F-MISO-PET imaging in patients with head and neck cancer in the course of primary chemoradiotherapy

BACKGROUND AND PURPOSE Hypoxia in head and neck tumours is associated with poor prognosis and outcome, and can be visualized using (18)F-MISO-PET imaging; however, it is not clear whether the size and location of hypoxic subvolumes remain stable during therapy. In a pilot project, we conducted an exploratory analysis of persistent tumour hypoxia during treatment. MATERIALS AND METHODS Sixteen patients with locally advanced head and neck tumours underwent consecutive (18)F-MISO-PET scans before and during primary chemoradiotherapy. The size, location and overlap of the hypoxic subvolumes were analysed using a semi-automatic algorithm based on a tumour to normal tissue ratio of 1.5. RESULTS Quantitative evaluation showed tumour hypoxia in week 0 in 16 out of 16 and in week 2 in 5 out of 14 patients. For the five patients with persistent hypoxia, both increased and decreased hypoxic subvolumes could be observed. Mean hypoxic subvolume overlap was 55% of the hypoxic volume of the first scan and 72% of the hypoxic volume of the second scan. A stationary (in four out of five patients) and dynamic component (in three out of five patients) could be differentiated. CONCLUSION In patients with persistent hypoxia after 2 weeks of treatment, the hypoxic subvolumes showed mostly a geographically relatively stable conformation.

Serial [18F]-fluoromisonidazole PET during radiochemotherapy for locally advanced head and neck cancer and its correlation with outcome.

PURPOSE The aim was to assess changes of tumour hypoxia during primary radiochemotherapy (RCT) for head and neck cancer (HNC) and to evaluate their relationship with treatment outcome. MATERIAL AND METHODS Hypoxia was assessed by FMISO-PET in weeks 0, 2 and 5 of RCT. The tumour volume (TV) was determined using FDG-PET/MRI/CT co-registered images. The level of hypoxia was quantified on FMISO-PET as TBRmax (SUVmaxTV/SUVmean background). The hypoxic subvolume (HSV) was defined as TV that showed FMISO uptake ⩾1.4 times blood pool activity. RESULTS Sixteen consecutive patients (T3-4, N+, M0) were included (mean follow-up 31, median 44months). Mean TBRmax decreased significantly (p<0.05) from 1.94 to 1.57 (week 2) and 1.27 (week 5). Mean HSV in week 2 and week 5 (HSV2=5.8ml, HSV3=0.3ml) were significantly (p<0.05) smaller than at baseline (HSV1=15.8ml). Kaplan-Meier plots of local recurrence free survival stratified at the median TBRmax showed superior local control for less hypoxic tumours, the difference being significant at baseline and after 2weeks (p=0.031, p=0.016). CONCLUSIONS FMISO-PET documented that in most HNC reoxygenation starts early during RCT and is correlated with better outcome.

Using a contextualized sensemaking model for interaction design

Sensemaking theories help designers understand the cognitive processes of a user when he/she performs a complicated task. This paper introduces a two-step approach of incorporating sensemaking support within the design of health information systems by: (1) modeling the sensemaking process of physicians while performing a task, and (2) identifying software interaction design requirements that support sensemaking based on this model. The two-step approach is presented based on a case study of the tumor contouring clinical task for radiotherapy planning. In the first step of the approach, a contextualized sensemaking model was developed to describe the sensemaking process based on the goal, the workflow and the context of the task. In the second step, based on a research software prototype, an experiment was conducted where three contouring tasks were performed by eight physicians respectively. Four types of navigation interactions and five types of interaction sequence patterns were identified by analyzing the gathered interaction log data from those twenty-four cases. Further in-depth study on each of the navigation interactions and interaction sequence patterns in relation to the contextualized sensemaking model revealed five main areas for design improvements to increase sensemaking support. Outcomes of the case study indicate that the proposed two-step approach was beneficial for gaining a deeper understanding of the sensemaking process during the task, as well as for identifying design requirements for better sensemaking support.

Clipping of tumour resection margins allows accurate target volume delineation in head and neck cancer adjuvant radiation therapy.

BACKGROUND Accurate tumour bed localisation is a key requirement for adjuvant radiotherapy. A new procedure is described for head and neck cancer treatment that improves tumour bed localisation using titanium clips. MATERIALS AND METHODS Following complete local excision of the primary tumour, the tumour bed was marked with titanium clips. Preoperative gross target volume (GTV) and postoperative tumour bed were examined and the distances between the centres of gravity were evaluated. RESULTS 49 patients with squamous cell carcinoma of the oral cavity were prospectively enrolled in this study. All patients underwent tumour resection, neck lymph node dissection and defect reconstruction in one stage. During surgery, 7-49 clips were placed in the resection cavity. Surgical clip insertion was successful in 88% (n=43). Clip identification and tumour bed delineation was successful in all 43 patients. The overall distance between the centres of gravity of the preoperative tumour extension to the tumour bed was 0.9cm. A significant relationship between the preoperative tumour extension and the postoperative tumour bed volume could be demonstrated. CONCLUSION We demonstrate a precise delineation of the former tumour cavity. Improvements in tumour bed delineation allow an increase of accuracy for adjuvant treatment.

A systematic review of antiproton radiotherapy

Antiprotons have been proposed as possible particles for radiotherapy; over the past years, the renewed interest in the potential biomedical relevance led to an increased research activity. It is the aim of this review to deliver a comprehensive overview regarding the evidence accumulated so far, analysing the background and depicting the current status of antiprotons in radiotherapy. A literature search has been conducted, including major scientific and commercial databases. All articles and a number of relevant conference abstracts published in the respective field have been included in this systematic review. The physical basis of antiproton radiotherapy is complex; however, the characterisation of the energy deposition profile supports its potential use in radiotherapy. Also the dosimetry improved considerably over the past few years. Regarding the biological properties, data on the effects on cells are presented; however, definite conclusions regarding the relative biological effectiveness cannot be made at the moment and radiobiological evidence of enhanced effectiveness remains scarce. In addition, there is new evidence supporting the potential imaging properties, for example for online dose verification. Clinical settings which might profit from the use of antiprotons have been further tracked. Judging from the evidence available so far, clinical constellations requiring optimal sparing in the entrance region of the beam and re-irradiations might profit most from antiproton radiotherapy. While several open questions remain to be answered, first steps towards a thorough characterisation of this interesting modality have been made.

EP-2059: Changes in hypoxia in serial F-MISO/PET-CT during chemoradiation in HNSCC

Material and Methods: The study cohort comprised 40 patients who underwent neoadjuvant radiochemotherapy (NRCT) for rectal cancer (28x1.8 Gy, 5 times weekly, concomitant with two cycles 5-FU-based chemotherapy). From each of those patients dermal fibroblasts were cultured from skin specimen gained outside of the radiotherapy planning target volume at occasion of surgery conducted about six weeks upon N-RCT completion. Acute radiotoxicity was thoroughly monitored throughout the N-RCT series and documented according to CTC classification. Maximal acute toxicity (MAT) was defined by the highest CTC grade of the four items “cystitis”, “proctitis”, “enteritis”, and “dermatitis”. MAT was grouped into grades 0/1 (n=16), 2 (n=16), and 3/4 (n=8). N-RCT was simulated in the cultured fibroblasts for five consecutive days (1.8 Gy each at d1-d5 with addiation of 5-FU at a concentration reflecting clinical steady-state levels) followed by a 7-day wash-out period. Gene expression of nine candidate genes (CAT, CDKN1A, CTGF, SMAD2/3/4/7, TGFB1, TGFBR1) supposed to mediate early radiation-induced toxicity was ascertained by quantitative real time PCR. Samples for these RNA analyses were harvested at d2 and d5 (each 4 hours upon application of the radiation fraction) as well as at day 12 upon the washout period. GAPDH and HPRT1 transcript levels served as reference.

EP-1086: Finding the right threshold for determining hypoxic subvolumes in F-MISO-PET/CTs for HNSCC

ESTRO 35 2016 _____________________________________________________________________________________________________ setting remains still controversial, despite the large consensus as a promising candidate to become a biomarker that could further improve application and efficacy of radiation therapy (RT) in head and neck squamous cell carcinoma (HNSCC). Moreover, most of the studies refer to series of patients who underwent RT alone or in combination with Cetuximab. We performed a retrospective analysis on the prognostic value of EGFR expression in HNSCC treated with surgery and postoperative RT.

PO-0650: Dynamics of tumor hypoxia in serial 18F-Misonidazole PET for SCCHN during chemoradiation and correlation to outcome

Conclusions: After definitive RT or CRT, five different patterns of swallowing dysfunction can be identified over time. This could reflect different underlying radiobiological mechanisms of radiation-induced damage and recovery. These results may improve identifying patients who are at the highest risk for developing severe persistent swallowing problems and who may benefit most from different preventive measures, such as swallowing sparing IMRT.