Kristin Stützer

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

PURPOSE The 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. METHODS AND MATERIALS For 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. RESULTS Generally, 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%. CONCLUSIONS Subgrouping 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.

Experimental verification of a 4D MLEM reconstruction algorithm used for in-beam PET measurements in particle therapy

In-beam positron emission tomography (PET) has been proven to be a reliable technique in ion beam radiotherapy for the in situ and non-invasive evaluation of the correct dose deposition in static tumour entities. In the presence of intra-fractional target motion an appropriate time-resolved (four-dimensional, 4D) reconstruction algorithm has to be used to avoid reconstructed activity distributions suffering from motion-related blurring artefacts and to allow for a dedicated dose monitoring. Four-dimensional reconstruction algorithms from diagnostic PET imaging that can properly handle the typically low counting statistics of in-beam PET data have been adapted and optimized for the characteristics of the double-head PET scanner BASTEI installed at GSI Helmholtzzentrum Darmstadt, Germany (GSI). Systematic investigations with moving radioactive sources demonstrate the more effective reduction of motion artefacts by applying a 4D maximum likelihood expectation maximization (MLEM) algorithm instead of the retrospective co-registration of phasewise reconstructed quasi-static activity distributions. Further 4D MLEM results are presented from in-beam PET measurements of irradiated moving phantoms which verify the accessibility of relevant parameters for the dose monitoring of intra-fractionally moving targets. From in-beam PET listmode data sets acquired together with a motion surrogate signal, valuable images can be generated by the 4D MLEM reconstruction for different motion patterns and motion-compensated beam delivery techniques.

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.

Required transition from research to clinical application: Report on the 4D treatment planning workshops 2014 and 2015

Since 2009, a 4D treatment planning workshop has taken place annually, gathering researchers working on the treatment of moving targets, mainly with scanned ion beams. Topics discussed during the workshops range from problems of time resolved imaging, the challenges of motion modelling, the implementation of 4D capabilities for treatment planning, up to different aspects related to 4D dosimetry and treatment verification. This report gives an overview on topics discussed at the 4D workshops in 2014 and 2015. It summarizes recent findings, developments and challenges in the field and discusses the relevant literature of the recent years. The report is structured in three parts pointing out developments in the context of understanding moving geometries, of treating moving targets and of 4D quality assurance (QA) and 4D dosimetry. The community represented at the 4D workshops agrees that research in the context of treating moving targets with scanned ion beams faces a crucial phase of clinical translation. In the coming years it will be important to define standards for motion monitoring, to establish 4D treatment planning guidelines and to develop 4D QA tools. These basic requirements for the clinical application of scanned ion beams to moving targets could e.g. be determined by a dedicated ESTRO task group. Besides reviewing recent research results and pointing out urgent needs when treating moving targets with scanned ion beams, the report also gives an outlook on the upcoming 4D workshop organized at the University Medical Center Groningen (UMCG) in the Netherlands at the end of 2016.

Dual-energy CT based proton range prediction in head and pelvic tumor patients

BACKGROUND AND PURPOSE To reduce range uncertainty in particle therapy, an accurate computation of stopping-power ratios (SPRs) based on computed tomography (CT) is crucial. Here, we assess range differences between the state-of-the-art CT-number-to-SPR conversion using a generic Hounsfield look-up table (HLUT) and a direct patient-specific SPR prediction (RhoSigma) based on dual-energy CT (DECT) in 100 proton treatment fields. MATERIAL AND METHODS For 25 head-tumor and 25 prostate-cancer patients, the clinically applied treatment plan, optimized using a HLUT, was recalculated with RhoSigma as CT-number-to-SPR conversion. Depth-dose curves in beam direction were extracted for both dose distributions in a regular grid and range deviations were determined and correlated to SPR differences within the irradiated volume. RESULTS Absolute (relative) mean water-equivalent range shifts of 1.1mm (1.2%) and 4.1mm (1.7%) were observed in the head-tumor and prostate-cancer cohort, respectively. Due to the case dependency of a generic HLUT, range deviations within treatment fields strongly depend on the tissues traversed leading to a larger variation within one patient than between patients. CONCLUSIONS The magnitude of patient-specific range deviations between HLUT and the more accurate DECT-based SPR prediction is clinically relevant. A clinical application of the latter seems feasible as demonstrated in this study using medically approved systems from CT acquisition to treatment planning.

Systematic analysis on the achievable accuracy of PT-PET through automated evaluation techniques.

INTRODUCTION Particle Therapy Positron Emission Tomography (PT-PET) is currently the only clinically applied method for in vivo verification of ion-beam radiotherapy during or close in time to the treatment. Since a direct deduction of the delivered dose from the measured activity is not feasible, images are compared to a reference distribution. The achievable accuracy of two image analysis approaches was investigated by means of reproducible phantom benchmark tests. This is an objective method that excludes patient related factors of influence. MATERIAL AND METHODS Two types of phantoms were designed to produce well defined deviations in the activity distributions. Pure range differences were simulated using the first phantom type while the other emulated cavity structures. The phantoms were irradiated with (12)C-ions. PT-PET measurements were performed by means of a camera system installed at the beamline. Different measurement time scenarios were investigated, assuming a PET scanner directly at the irradiation site or placed within the treatment room. The images were analyzed by means of the Pearson Correlation Coefficient (PCC) and a range calculation algorithm combined with a dedicated cavity filling detection method. RESULTS Range differences could be measured with an error of less than 2 mm. The range comparison algorithm yielded slightly better results than the PCC method. The filling of a cavity structure could be safely detected if its inner diameter was at least 5 mm. CONCLUSION Both approaches evaluate the PT-PET data in an objective way and deliver promising results for in-beam and in-room PET for clinical realistic dose rates.

Increase in Tumor Control and Normal Tissue Complication Probabilities in Advanced Head-and-Neck Cancer for Dose-Escalated Intensity-Modulated Photon and Proton Therapy

Introduction Presently used radiochemotherapy regimens result in moderate local control rates for patients with advanced head-and-neck squamous cell carcinoma (HNSCC). Dose escalation (DE) may be an option to improve patient outcome, but may also increase the risk of toxicities in healthy tissue. The presented treatment planning study evaluated the feasibility of two DE levels for advanced HNSCC patients, planned with either intensity-modulated photon therapy (IMXT) or proton therapy (IMPT). Materials and methods For 45 HNSCC patients, IMXT and IMPT treatment plans were created including DE via a simultaneous integrated boost (SIB) in the high-risk volume, while maintaining standard fractionation with 2 Gy per fraction in the remaining target volume. Two DE levels for the SIB were compared: 2.3 and 2.6 Gy. Treatment plan evaluation included assessment of tumor control probabilities (TCP) and normal tissue complication probabilities (NTCP). Results An increase of approximately 10% in TCP was estimated between the DE levels. A pronounced high-dose rim surrounding the SIB volume was identified in IMXT treatment. Compared to IMPT, this extra dose slightly increased the TCP values and to a larger extent the NTCP values. For both modalities, the higher DE level led only to a small increase in NTCP values (mean differences <2%) in all models, except for the risk of aspiration, which increased on average by 8 and 6% with IMXT and IMPT, respectively, but showed a considerable patient dependence. Conclusion Both DE levels appear applicable to patients with IMXT and IMPT since all calculated NTCP values, except for one, increased only little for the higher DE level. The estimated TCP increase is of relevant magnitude. The higher DE schedule needs to be investigated carefully in the setting of a prospective clinical trial, especially regarding toxicities caused by high local doses that lack a sound dose–response description, e.g., ulcers.

Experimental investigation of irregular motion impact on 4D PET-based particle therapy monitoring

Particle therapy positron emission tomography (PT-PET) is an in vivo and non-invasive imaging technique to monitor treatment delivery in particle therapy. The inevitable patient respiratory motion during irradiation causes artefacts and inaccurate activity distribution in PET images. Four-dimensional (4D) maximum likelihood expectation maximisation (4D MLEM) allows for a compensation of these effects, but has up to now been restricted to regular motion for PT-PET investigations. However, intra-fractional motion during treatment might differ from that during acquisition of the 4D-planning CT (e.g. amplitude variation, baseline drift) and therefore might induce inaccurate 4D PET reconstruction results. This study investigates the impact of different irregular analytical one-dimensional (1D) motion patterns on PT-PET imaging by means of experiments with a radioactive source and irradiated moving phantoms. Three sorting methods, namely phase sorting, equal amplitude sorting and event-based amplitude sorting, were applied to manage the PET list-mode data. The influence of these sorting methods on the motion compensating algorithm has been analysed. The event-based amplitude sorting showed a superior performance and it is applicable for irregular motions with ⩽ 4 mm amplitude elongation and drift. For motion with 10 mm baseline drift, the normalised root mean square error was as high as 10.5% and a 10 mm range deviation was observed.

4D offline PET-based treatment verification in scanned ion beam therapy: a phantom study.

At the Heidelberg Ion-Beam Therapy Center, patient irradiation with scanned proton and carbon ion beams is verified by offline positron emission tomography (PET) imaging: the β+-activity measured within the patient is compared to a prediction calculated on the basis of the treatment planning data in order to identify potential delivery errors. Currently, this monitoring technique is limited to the treatment of static target structures. However, intra-fractional organ motion imposes considerable additional challenges to scanned ion beam radiotherapy. In this work, the feasibility and potential of time-resolved (4D) offline PET-based treatment verification with a commercial full-ring PET/CT (x-ray computed tomography) device are investigated for the first time, based on an experimental campaign with moving phantoms. Motion was monitored during the gated beam delivery as well as the subsequent PET acquisition and was taken into account in the corresponding 4D Monte-Carlo simulations and data evaluation. Under the given experimental conditions, millimeter agreement between the prediction and measurement was found. Dosimetric consequences due to the phantom motion could be reliably identified. The agreement between PET measurement and prediction in the presence of motion was found to be similar as in static reference measurements, thus demonstrating the potential of 4D PET-based treatment verification for future clinical applications.