Robert Haase

Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer

PURPOSEnTo explore in a prospective trial the prognostic value of hypoxia imaging before and during radiochemotherapy in patients with locally advanced head and neck cancer.nnnPATIENTS AND METHODSnTwenty-five patients with stage III/IV head and neck cancer were investigated with [(18)F]-fluoromisonidazole (FMISO) PET/CT at four time points during radiochemotherapy (baseline, 8-10 Gy, 18-20 Gy,50-60 Gy). FMISO PET/CT image parameters were extracted including maximum-tumour-to-background (TBR(max)) and thresholded volume at different TBR ratios. CT volume and baseline FDG-PET/CT image parameters were also included. Parameters at all time points were investigated for their prognostic value with the local-progression-free-survival endpoint (LPFS). Significance was evaluated with multivariate Cox (including clinical parameters) and Log-rank tests.nnnRESULTSnFMISO-image parameters were found to have a strong association with the LPFS endpoint, and were strongest at the week 1 and 2 time points (p = 0.023-0.048 and 0.042-0.061 respectively on multivariate Cox). Parameters measured at baseline were only significant on univariate analysis. None of the clinical parameters, and also FDG- or CT-delineated volumes, were significantly associated with LPFS.nnnCONCLUSIONnThis prospective, exploratory study demonstrated that FMISO-PET/CT imaging during the initial phase of treatment carries strong prognostic value. FMISO-PET/CT imaging at 1 or 2 weeks during treatment could be promising way to select patients that would benefit from hypoxia modification or dose-escalated treatment. A validation study is on-going.

Identification of Patient Benefit From Proton Therapy for Advanced Head and Neck Cancer Patients Based on Individual and Subgroup Normal Tissue Complication Probability Analysis

PURPOSEnThe purpose of this study was to determine, by treatment plan comparison along with normal tissue complication probability (NTCP) modeling, whether a subpopulation of patients with head and neck squamous cell carcinoma (HNSCC) could be identified that would gain substantial benefit from proton therapy in terms of NTCP.nnnMETHODS AND MATERIALSnFor 45 HNSCC patients, intensity modulated radiation therapy (IMRT) was compared to intensity modulated proton therapy (IMPT). Physical dose distributions were evaluated as well as the resulting NTCP values, using modern models for acute mucositis, xerostomia, aspiration, dysphagia, laryngeal edema, and trismus. Patient subgroups were defined based on primary tumor location.nnnRESULTSnGenerally, IMPT reduced the NTCP values while keeping similar target coverage for all patients. Subgroup analyses revealed a higher individual reduction of swallowing-related side effects by IMPT for patients with tumors in the upper head and neck area, whereas the risk reduction of acute mucositis was more pronounced in patients with tumors in the larynx region. More patients with tumors in the upper head and neck area had a reduction in NTCP of more than 10%.nnnCONCLUSIONSnSubgrouping can help to identify patients who may benefit more than others from the use of IMPT and, thus, can be a useful tool for a preselection of patients in the clinic where there are limited PT resources. Because the individual benefit differs within a subgroup, the relative merits should additionally be evaluated by individual treatment plan comparisons.

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.

Precise image-guided irradiation of small animals: a flexible non-profit platform.

Preclinical in vivo studies using small animals are essential to develop new therapeutic options in radiation oncology. Of particular interest are orthotopic tumour models, which better reflect the clinical situation in terms of growth patterns and microenvironmental parameters of the tumour as well as the interplay of tumours with the surrounding normal tissues. Such orthotopic models increase the technical demands and the complexity of preclinical studies as local irradiation with therapeutically relevant doses requires image-guided target localisation and accurate beam application. Moreover, advanced imaging techniques are needed for monitoring treatment outcome. We present a novel small animal image-guided radiation therapy (SAIGRT) system, which allows for precise and accurate, conformal irradiation and x-ray imaging of small animals. High accuracy is achieved by its robust construction, the precise movement of its components and a fast high-resolution flat-panel detector. Field forming and x-ray imaging is accomplished close to the animal resulting in a small penumbra and a high image quality. Feasibility for irradiating orthotopic models has been proven using lung tumour and glioblastoma models in mice. The SAIGRT system provides a flexible, non-profit academic research platform which can be adapted to specific experimental needs and therefore enables systematic preclinical trials in multicentre research networks.

NTCP reduction for advanced head and neck cancer patients using proton therapy for complete or sequential boost treatment versus photon therapy.

ABSTRACT Background. To determine by treatment plan comparison differences in toxicity risk reduction for patients with head and neck squamous cell carcinoma (HNSCC) from proton therapy either used for complete treatment or sequential boost treatment only. Materials and methods. For 45 HNSCC patients, intensity-modulated photon (IMXT) and proton (IMPT) treatment plans were created including a dose escalation via simultaneous integrated boost with a one-step adaptation strategy after 25 fractions for sequential boost treatment. Dose accumulation was performed for pure IMXT treatment, pure IMPT treatment and for a mixed modality treatment with IMXT for the elective target followed by a sequential boost with IMPT. Treatment plan evaluation was based on modern normal tissue complication probability (NTCP) models for mucositis, xerostomia, aspiration, dysphagia, larynx edema and trismus. Individual NTCP differences between IMXT and IMPT (∆NTCPIMXT-IMPT) as well as between IMXT and the mixed modality treatment (∆NTCPIMXT-Mix) were calculated. Results. Target coverage was similar in all three scenarios. NTCP values could be reduced in all patients using IMPT treatment. However, ∆NTCPIMXT-Mix values were a factor 2–10 smaller than ∆NTCPIMXT-IMPT. Assuming a threshold of ≥ 10% NTCP reduction in xerostomia or dysphagia risk as criterion for patient assignment to IMPT, less than 15% of the patients would be selected for a proton boost, while about 50% would be assigned to pure IMPT treatment. For mucositis and trismus, ∆NTCP ≥ 10% occurred in six and four patients, respectively, with pure IMPT treatment, while no such difference was identified with the proton boost. Conclusions. The use of IMPT generally reduces the expected toxicity risk while maintaining good tumor coverage in the examined HNSCC patients. A mixed modality treatment using IMPT solely for a sequential boost reduces the risk by 10% only in rare cases. In contrast, pure IMPT treatment may be reasonable for about half of the examined patient cohort considering the toxicities xerostomia and dysphagia, if a feasible strategy for patient anatomy changes is implemented.

Swarm intelligence for medical volume segmentation: the contribution of self-reproduction

For special applications in diagnostics for oncology the analysis of imaging data from Positron Emission Tomography (PET) is obfuscated by low contrast and high noise. To deal with this issue we propose a segmentation algorithm based on Ant Colony Optimization (ACO) and evolutionary selection of ants for self reproduction. The self reproduction approach is no standard for ACO, but appears to be crucial for volume segmentation. This investigation was focused on two different ways for reproduction control and their contribution to quantity and quality of segmentation results. One of the evaluated methods appears to be able to replace the explicit ant movement through transition rules by implicit movement through reproduction. Finally the combination of transition rules and self reproduction generates best reproducible segmentation results.

Self-reproduction versus transition rules in ant colonies for medical volume segmentation

Target volume delineation in image stacks resulting from low contrast positron emission tomography (PET) remains a hot topic in the field of medical image processing. We propose an algorithm based on artificial ants moving in three dimensional image space controlled by transition rules which are able to self-reproduce. This investigation shows by variation of the transition rules that the impact on segmentation results is small because self-reproduction is the overwhelming effect in the simulation.

Evaluation of a deformable registration algorithm for subsequent lung computed tomography imaging during radiochemotherapy

PURPOSEnRating both a lung segmentation algorithm and a deformable image registration (DIR) algorithm for subsequent lung computed tomography (CT) images by different evaluation techniques. Furthermore, investigating the relative performance and the correlation of the different evaluation techniques to address their potential value in a clinical setting.nnnMETHODSnTwo to seven subsequent CT images (69 in total) of 15 lung cancer patients were acquired prior, during, and after radiochemotherapy. Automated lung segmentations were compared to manually adapted contours. DIR between the first and all following CT images was performed with a fast algorithm specialized for lung tissue registration, requiring the lung segmentation as input. DIR results were evaluated based on landmark distances, lung contour metrics, and vector field inconsistencies in different subvolumes defined by eroding the lung contour. Correlations between the results from the three methods were evaluated.nnnRESULTSnAutomated lung contour segmentation was satisfactory in 18 cases (26%), failed in 6 cases (9%), and required manual correction in 45 cases (66%). Initial and corrected contours had large overlap but showed strong local deviations. Landmark-based DIR evaluation revealed high accuracy compared to CT resolution with an average error of 2.9 mm. Contour metrics of deformed contours were largely satisfactory. The median vector length of inconsistency vector fields was 0.9 mm in the lung volume and slightly smaller for the eroded volumes. There was no clear correlation between the three evaluation approaches.nnnCONCLUSIONSnAutomatic lung segmentation remains challenging but can assist the manual delineation process. Proven by three techniques, the inspected DIR algorithm delivers reliable results for the lung CT data sets acquired at different time points. Clinical application of DIR demands a fast DIR evaluation to identify unacceptable results, for instance, by combining different automated DIR evaluation methods.

FMISO-PET-based lymph node hypoxia adds to the prognostic value of tumor only hypoxia in HNSCC patients

PURPOSEnThis secondary analysis of the prospective study on repeat [18F]fluoromisonidazole (FMISO)-PET in patients with locally advanced head and neck squamous cell carcinomas (HNSCC) assessed the prognostic value of synchronous hypoxia in primary tumor (Tu) and lymph node metastases (LN), and evaluated whether the combined reading was of higher prognostic value than that of primary tumor hypoxia only.nnnMETHODSnThis analysis included forty-five LN-positive HNSCC patients. FMISO-PET/CTs were performed at baseline, weeks 1, 2 and 5 of radiochemotherapy. Based on a binary scale, Tu and LN were categorized as hypoxic or normoxic, and two prognostic parameters were defined: Tu-hypoxia (independent of the LN oxygenation status) and synchronous Tu-and-LN-hypoxia. In fifteen patients with large LN (Nu202f=u202f21), additional quantitative analyses of FMISO-PET/CTs were performed. Imaging parameters at different time-points were correlated to the endpoints, i.e., locoregional control (LRC), local control (LC), regional control (RC) and time to progression (TTP). Survival curves were estimated using the cumulative incidence function. Univariable and multivariable Cox regression was used to evaluate the prognostic impact of hypoxia on the endpoints.nnnRESULTSnSynchronous Tu-and-LN-hypoxia was a strong adverse prognostic factor for LC, LRC and TTP at any of the four time-points (pu202f≤u202f0.004), whereas Tu-hypoxia only was significantly associated with poor LC and LRC in weeks 2 and 5 (pu202f≤u202f0.047), and with TTP in week 1 (pu202f=u202f0.046). The multivariable analysis confirmed the prognostic value of synchronous Tu-and-LN-hypoxia regarding LRC (HRu202f=u202f14.8, pu202f=u202f0.017). The quantitative FMISO-PET/CT parameters correlated with qualitative hypoxia scale and RC (pu202f<u202f0.001, pu202f≤u202f0.033 at week 2, respectively).nnnCONCLUSIONSnThis secondary analysis suggests that combined reading of primary tumor and LN hypoxia adds to the prognostic information of FMSIO-PET in comparison to primary tumor assessment alone in particular prior and early during radiochemotherapy. Confirmation in ongoing trials is needed before using this marker for personalized radiation oncology.

On the Reliability of Automatic Volume Delineation in Low-Contrast [(18)F]FMISO-PET Imaging.

Hypoxia is a marker of poor prognosis in malignant tumors independent from the selected therapeutic method and the therapy should be intensified in such tumors. Hypoxia imaging with positron emission tomography (PET) is limited by low contrast to noise ratios with every available tracer. In radiation oncology appropriate delineation is required to allow therapy and intensification. While manual segmentation results are highly dependent from experience and observers condition (high inter- and intra observer variability), threshold- and gradient-based algorithms for automatic segmentation frequently fail in low contrast data sets. Likewise, calibration of these algorithms using phantoms is not useful. Complex computational models such as swarm intelligence-based algorithms are promising tools for optimized segmentation results and allow observer independent interpretation of multimodal and multidimensional imaging data.