Annika Jakobi

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.

Particle Therapy for Non-Small Cell Lung Tumors: Where Do We Stand? A Systematic Review of the Literature

This review article provides a systematic overview of the currently available evidence on the clinical effectiveness of particle therapy for the treatment of non-small cell lung cancer and summarizes findings of in silico comparative planning studies. Furthermore, technical issues and dosimetric uncertainties with respect to thoracic particle therapy are discussed.

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.

Concept for individualized patient allocation: ReCompare--remote comparison of particle and photon treatment plans.

BackgroundIdentifying those patients who have a higher chance to be cured with fewer side effects by particle beam therapy than by state-of-the-art photon therapy is essential to guarantee a fair and sufficient access to specialized radiotherapy. The individualized identification requires initiatives by particle as well as non-particle radiotherapy centers to form networks, to establish procedures for the decision process, and to implement means for the remote exchange of relevant patient information. In this work, we want to contribute a practical concept that addresses these requirements.MethodsWe proposed a concept for individualized patient allocation to photon or particle beam therapy at a non-particle radiotherapy institution that bases on remote treatment plan comparison. We translated this concept into the web-based software tool ReCompare (REmote COMparison of PARticlE and photon treatment plans).ResultsWe substantiated the feasibility of the proposed concept by demonstrating remote exchange of treatment plans between radiotherapy institutions and the direct comparison of photon and particle treatment plans in photon treatment planning systems. ReCompare worked with several tested standard treatment planning systems, ensured patient data protection, and integrated in the clinical workflow.ConclusionsOur concept supports non-particle radiotherapy institutions with the patient-specific treatment decision on the optimal irradiation modality by providing expertise from a particle therapy center. The software tool ReCompare may help to improve and standardize this personalized treatment decision. It will be available from our website when proton therapy is operational at our facility.

Implementation of a software for REmote COMparison of PARticlE and photon treatment plans: ReCompare

PURPOSE To guarantee equal access to optimal radiotherapy, a concept of patient assignment to photon or particle radiotherapy using remote treatment plan exchange and comparison - ReCompare - was proposed. We demonstrate the implementation of this concept and present its clinical applicability. MATERIALS AND METHODS The ReCompare concept was implemented using a client-server based software solution. A clinical workflow for the remote treatment plan exchange and comparison was defined. The steps required by the user and performed by the software for a complete plan transfer were described and an additional module for dose-response modeling was added. RESULTS The ReCompare software was successfully tested in cooperation with three external partner clinics and worked meeting all required specifications. It was compatible with several standard treatment planning systems, ensured patient data protection, and integrated in the clinical workflow. CONCLUSION The ReCompare software can be applied to support non-particle radiotherapy institutions with the patient-specific treatment decision on the optimal irradiation modality by remote treatment plan exchange and comparison.

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.

Feasibility of proton pencil beam scanning treatment of free-breathing lung cancer patients

Abstract Background: The interplay effect might degrade the dose of pencil beam scanning proton therapy to a degree that free-breathing treatment might be impossible without further motion mitigation techniques, which complicate and prolong the treatment. We assessed whether treatment of free-breathing patients without motion mitigation is feasible. Material and methods: For 40 lung cancer patients, 4DCT datasets and individual breathing patterns were used to simulate 4D dynamic dose distributions of 3D treatment plans over 33 fractions delivered with an IBA universal nozzle. Evaluation was done by assessing under- and overdosage in the target structure using the parameters V90, V95, V98, D98, D2, V107 and V110. The impact of using beam-specific target volumes and the impact of changes in motion and patient anatomy in control 4DCTs were assessed. Results: Almost half of the patients had tumour motion amplitudes of less than 5 mm. Under- and overdosage was significantly smaller for patients with tumour motion below 5 mm compared to patients with larger motion (2% vs. 13% average absolute reduction of V95, 2% vs. 8% average increase in V107, p < .01). Simulating a 33-fraction treatment, the dose degradation was reduced but persisted for patients with tumour motion above 5 mm (average ΔV95 of <1% vs. 3%, p < .01). Beam-specific target volumes reduced the dose degradation in a fractionated treatment, but were more relevant for large motion. Repeated 4DCT revealed that changes in tumour motion during treatment might result in unexpected large dose degradations. Conclusion: Tumour motion amplitude is an indicator of dose degradation caused by the interplay effect. Fractionation reduces the dose degradation allowing the unmitigated treatment of patients with small tumour motions of less than 5 mm. The beam-specific target approach improves the dose coverage. The tumour motion and position needs to be assessed during treatment for all patients, to quickly react to possible changes, which might require treatment adaptation.

Potential proton and photon dose degradation in advanced head and neck cancer patients by intratherapy changes

Abstract Purpose Evaluation of dose degradation by anatomic changes for head‐and‐neck cancer (HNC) intensity‐modulated proton therapy (IMPT) relative to intensity‐modulated photon therapy (IMRT) and identification of potential indicators for IMPT treatment plan adaptation. Methods For 31 advanced HNC datasets, IMPT and IMRT plans were recalculated on a computed tomography scan (CT) taken after about 4 weeks of therapy. Dose parameter changes were determined for the organs at risk (OARs) spinal cord, brain stem, parotid glands, brachial plexus, and mandible, for the clinical target volume (CTV) and the healthy tissue outside planning target volume (PTV). Correlation of dose degradation with target volume changes and quality of rigid CT matching was investigated. Results Recalculated IMPT dose distributions showed stronger degradation than the IMRT doses. OAR analysis revealed significant changes in parotid median dose (IMPT) and near maximum dose (D 1ml) of spinal cord (IMPT, IMRT) and mandible (IMPT). OAR dose parameters remained lower in IMPT cases. CTV coverage (V 95%) and overdose (V 107%) deteriorated for IMPT plans to (93.4 ± 5.4)% and (10.6 ± 12.5)%, while those for IMRT plans remained acceptable. Recalculated plans showed similarly decreased PTV conformity, but considerable hotspots, also outside the PTV, emerged in IMPT cases. Lower CT matching quality was significantly correlated with loss of PTV conformity (IMPT, IMRT), CTV homogeneity and coverage (IMPT). Target shrinkage correlated with increased dose in brachial plexus (IMRT, IMPT), hotspot generation outside the PTV (IMPT) and lower PTV conformity (IMRT). Conclusions The study underlines the necessity of precise positioning and monitoring of anatomy changes, especially in IMPT which might require adaptation more often. Since OAR doses remained typically below constraints, IMPT plan adaptation will be indicated by target dose degradations.

Modeling tumor control probability for spatially inhomogeneous risk of failure based on clinical outcome data

PURPOSE Objectives of this work are (1) to derive a general clinically relevant approach to model tumor control probability (TCP) for spatially variable risk of failure and (2) to demonstrate its applicability by estimating TCP for patients planned for photon and proton irradiation. METHODS AND MATERIALS The approach divides the target volume into sub-volumes according to retrospectively observed spatial failure patterns. The product of all sub-volume TCPi values reproduces the observed TCP for the total tumor. The derived formalism provides for each target sub-volume i the tumor control dose (D50,i) and slope (γ50,i) parameters at 50% TCPi. For a simultaneous integrated boost (SIB) prescription for 45 advanced head and neck cancer patients, TCP values for photon and proton irradiation were calculated and compared. The target volume was divided into gross tumor volume (GTV), surrounding clinical target volume (CTV), and elective CTV (CTVE). The risk of a local failure in each of these sub-volumes was taken from the literature. RESULTS Convenient expressions for D50,i and γ50,i were provided for the Poisson and the logistic model. Comparable TCP estimates were obtained for photon and proton plans of the 45 patients using the sub-volume model, despite notably higher dose levels (on average +4.9%) in the low-risk CTVE for photon irradiation. In contrast, assuming a homogeneous dose response in the entire target volume resulted in TCP estimates contradicting clinical experience (the highest failure rate in the low-risk CTVE) and differing substantially between photon and proton irradiation. CONCLUSIONS The presented method is of practical value for three reasons: It (a) is based on empirical clinical outcome data; (b) can be applied to non-uniform dose prescriptions as well as different tumor entities and dose-response models; and (c) is provided in a convenient compact form. The approach may be utilized to target spatial patterns of local failures observed in patient cohorts by prescribing different doses to different target regions. Its predictive power depends on the uncertainty of the employed established TCP parameters D50 and γ50 and to a smaller extent on that of the clinically observed pattern of failure risk.