Sebastian Zschaeck

Spatial distribution of FMISO in head and neck squamous cell carcinomas during radio-chemotherapy and its correlation to pattern of failure

ABSTRACT Background. Tumour hypoxia can be measured by FMISO-PET and negatively impacts local tumour control in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy. The aim of this post hoc analysis of a prospective clinical trial was to investigate the spatial variability of FMISO hypoxic subvolumes during radio-chemotherapy and the co-localisation of these volumes with later recurrences as a basis for individualised dose prescription trials with dose escalation defined by FMISO-PET. Methods. Sequential FMISO scans of 12 (of 25) patients presenting residual hypoxia taken before (FMISOpre) and during (FMISOw1–FMISOw5) radio-chemotherapy were analysed regarding the stability of the FMISO subvolumes and, in case of local failure, their correlation to local relapse. Results. Consecutive FMISO-PET positive volumes could be classified as moderately stable with Dice conformity indices of 62% and 58% up to the second week of treatment. Substantial volumetric variation during treatment was observed, with more than 20% geographic miss in all patients and more than 40% in half of the patients. The localisation of the maximum standardised uptake value (SUVmax) differed with a mean distance of 7.0 mm and 13.5 mm between the pre-therapeutic and first or second FMISO-PET during treatment. A stable hypoxic consensual volume (i.e. overlap of pre-therapeutic FMISO and intra-treatment FMISO subvolumes up to week two, generated by different contouring methods) was determined for six patients with imaging information of local recurrence. Three of these six local recurrences were located within this consensual volume. Conclusions. Our data suggest that selective dose painting to hypoxic tumour subvolumes requires adaptation during treatment and sufficient margins. An alternative strategy is to escalate the dose to the gross tumour volume, accepting lesser escalation of dose outside hypoxic areas if indicated by constraints for organs at risk.

Residual tumour hypoxia in head-and-neck cancer patients undergoing primary radiochemotherapy, final results of a prospective trial on repeat FMISO-PET imaging

BACKGROUND Hypoxia is a well recognised parameter of tumour resistance to radiotherapy, a number of anticancer drugs and potentially immunotherapy. In a previously published exploration cohort of 25 head and neck squamous cell carcinoma (HNSCC) patients on [18F]fluoromisonidazole positron emission tomography (FMISO-PET) we identified residual tumour hypoxia during radiochemotherapy, not before start of treatment, as the driving mechanism of hypoxia-mediated therapy resistance. Several quantitative FMISO-PET parameters were identified as potential prognostic biomarkers. Here we present the results of the prospective validation cohort, and the overall results of the study. METHODS FMISO-PET/CT images of further 25 HNSCC patients were acquired at four time-points before and during radiochemotherapy (RCHT). Peak standardised uptake value, tumour-to-background ratio, and hypoxic volume were analysed. The impact of the potential prognostic parameters on loco-regional tumour control (LRC) was validated by the concordance index (ci) using univariable and multivariable Cox models based on the exploration cohort. Log-rank tests were employed to compare the endpoint between risk groups. RESULTS The two cohorts differed significantly in several baseline parameters, e.g., tumour volume, hypoxic volume, HPV status, and intercurrent death. Validation was successful for several FMISO-PET parameters and showed the highest performance (ci=0.77-0.81) after weeks 1 and 2 of treatment. Cut-off values for the FMISO-PET parameters could be validated after week 2 of RCHT. Median values for the residual hypoxic volume, defined as the ratio of the hypoxic volume in week 2 of RCHT and at baseline, stratified patients into groups of significantly different LRC when applied to the respective other cohort. CONCLUSION Our study validates that residual tumour hypoxia during radiochemotherapy is a major driver of therapy resistance of HNSCC, and that hypoxia after the second week of treatment measured by FMISO-PET may serve as biomarker for selection of patients at high risk of loco-regional recurrence after state-of-the art radiochemotherapy.

Prognostic value of SUR in patients with trimodality treatment of locally advanced esophageal carcinoma

The prognosis of patients with esophageal carcinoma remains dismal despite ongoing efforts to improve treatment options. For locally advanced tumors, several randomized trials have shown the benefit of neoadjuvant chemoradiation followed by surgery compared with surgery alone. The aim of this exploratory study was to evaluate the prognostic value of different baseline PET parameters and their potentially additional prognostic impact at the end of neoadjuvant radiochemotherapy. Furthermore, the standardized uptake ratio (SUR) as a new parameter for quantification of tumor metabolism was compared with the conventional PET parameters metabolically active tumor volume (MTV), total lesion glycolysis (TLG), and SUV, taking into account known basic parameters. Methods: 18F-FDG PET/CT was performed on 76 consecutive patients (60 ± 10 y old, 71 men) with newly diagnosed esophageal cancer before and during the last week of neoadjuvant radiochemotherapy. MTV of the primary tumor was delineated with an adaptive threshold method. The blood SUV was determined by manually delineating the aorta in the low-dose CT scan. SURs were computed as the scan time–corrected ratio of tumor SUVmax and mean blood SUV. Univariate Cox regression and Kaplan–Meier analysis with respect to locoregional control (LRC), freedom from distant metastases (FFDM), and overall survival (OS) was performed. Additionally, the independence of PET parameters from standard clinical factors was analyzed with multivariate Cox regression. Results: In multivariate analysis, 2 parameters showed a significant correlation with all endpoints: restaging MTV and restaging SUR. Furthermore, restaging TLG was prognostic for LRC and FFDM. For all endpoints, the largest effect size was found for restaging SUR. The only basic factors remaining significant in multivariate analyses were histology for OS and FFDM and age for LRC. Conclusion: PET provides independent prognostic information for OS, LRC, and FFDM in addition to standard clinical parameters in this patient cohort. Our results suggest that the prognostic value of tracer uptake can be improved when characterized by SUR rather than by SUV. Overall, our investigation revealed a higher prognostic value for restaging parameters than for baseline PET; therapy adjustments would still be possible at that time. Further investigations are required to confirm these hypothesis-generating results.

CT imaging during treatment improves radiomic models for patients with locally advanced head and neck cancer

BACKGROUND AND PURPOSE The development of radiomic risk models to predict clinical outcome is usually based on pre-treatment imaging, such as computed tomography (CT) scans used for radiation treatment planning. Imaging data acquired during the course of treatment may improve their prognostic performance. We compared the performance of radiomic risk models based on the pre-treatment CT and CT scans acquired in the second week of therapy. MATERIAL AND METHODS Treatment planning and second week CT scans of 78 head and neck squamous cell carcinoma patients treated with primary radiochemotherapy were collected. 1538 image features were extracted from each image. Prognostic models for loco-regional tumour control (LRC) and overall survival (OS) were built using 6 feature selection methods and 6 machine learning algorithms. Prognostic performance was assessed using the concordance index (C-Index). Furthermore, patients were stratified into risk groups and differences in LRC and OS were evaluated by log-rank tests. RESULTS The performance of radiomic risk model in predicting LRC was improved using the second week CT scans (C-Index: 0.79), in comparison to the pre-treatment CT scans (C-Index: 0.65). This was confirmed by Kaplan-Meier analyses, in which risk stratification based on the second week CT could be improved for LRC (p = 0.002) compared to pre-treatment CT (p = 0.063). CONCLUSION Incorporation of imaging during treatment may be a promising way to improve radiomic risk models for clinical treatment adaption, i.e., to select patients that may benefit from dose modification.

Radiofrequency applicator concepts for simultaneous MR imaging and hyperthermia treatment of glioblastoma multiforme

Abstract Glioblastoma multiforme is the most frequent and most aggressive malignant brain tumor with de facto no long term curation by the use of current multimodal therapeutic approaches. The efficacy of brachytherapy and enhancing interstitial hyperthermia has been demonstrated. RF heating at ultrahigh fields (B0=7.0T, f=298MHz) has the potential of delivering sufficiently large thermal dosage for hyperthermia of relatively large tumor areas. This work focuses on electromagnetic field (EMF) simulations and provides realistic applicator designs tailored for simultaneous RF heating and MRI. Our simulations took advantage of target volumes derived from patient data, and our preliminary results suggest that RF power can be focused to both a small tumor area and a large clinical target volume.

Abskopale Effekte nach Strahlentherapie in Kombination mit GM-CSF

Hintergrund In einem vor Kurzem in Strahlentherapie und Onkologie bereits von Panje und Guckenberger veröffentlichten Literaturkommentar [1] wurde eine Studie von Golden und Kollegen [2] vorgestellt, die sich mit dem abskopalen Effekt der Strahlentherapie, d. h. einer Tumorwirkung außerhalb des Bestrahlungsfelds aufgrund immunologischer Wirkmechanismen, auseinandersetzt. Die Autoren vermuteten einen Vorteil durch die Gabe von GM-CSF, jedoch könne dies aufgrund fehlender Kontrollarme ohne diese Behandlung nicht sicher geschlussfolgert werden.

FMISO as a Biomarker for Clinical Radiation Oncology

Tumour hypoxia is a well-known negative prognostic marker in almost all solid tumours. [18F]Fluoromisonidazole (FMISO)-positron emission tomography (PET) is a non-invasive method to detect tumour hypoxia. Compared to other methods of hypoxia assessment it possesses some considerable advantages: It is non-invasive, it delivers spatial information on the hypoxia distribution within the entire tumour volume, and it can be repeated during the course of radio(chemo)therapy. This chapter briefly describes different methods of hypoxia evaluation and focuses on hypoxia PET imaging, with the most commonly used tracer being FMISO. The preclinical rationale and clinical studies to use FMISO-PET for patient stratification in radiation therapy are discussed as well as possible agents or radiation-dose modifications to overcome hypoxia.