Case Report: Treatment Planning Study to Demonstrate Feasibility of Transthoracic Ultrasound Guidance to Facilitate Ventricular Tachycardia Ablation With Protons.

Background: Cardiac arrhythmias, such as ventricular tachycardia, are disruptions in the normal cardiac function that originate from problems in the electrical conduction of signals inside the heart. Recently, a non-invasive treatment option based on external photon or proton beam irradiation has been used to ablate the arrhythmogenic structures. Especially in proton therapy, based on its steep dose gradient, it is crucial to monitor the motion of the heart in order to ensure that the radiation dose is delivered to the correct location. Transthoracic ultrasound imaging has the potential to provide guidance during this treatment delivery. However, it has to be noted that the presence of an ultrasound probe on the chest of the patient introduces constraints on usable beam angles for both protons and photon treatments. This case report investigates the possibility to generate a clinically acceptable proton treatment plan while the ultrasound probe is present on the chest of the patient. Case: A treatment plan study was performed based on a 4D cardiac-gated computed tomography scan of a 55 year-old male patient suffering from refractory ventricular tachycardia who underwent cardiac radioablation. A proton therapy treatment plan was generated for the actual treatment target in presence of an ultrasound probe on the chest of this patient. The clinical acceptability of the generated plan was confirmed by evaluating standard target dose-volume metrics, dose to organs-at-risk and target dose conformity and homogeneity. Conclusion: The generation of a clinically acceptable proton therapy treatment plan for cardiac radioablation of ventricular tachycardia could be performed in the presence of an ultrasound probe on the chest of the patient. These results establish a basis and justification for continued research and product development for ultrasound-guided cardiac radioablation.

Implementation of a dedicated 1.5 T MR scanner for radiotherapy treatment planning featuring a novel high-channel coil setup for brain imaging in treatment position.

PURPOSE: To share our experiences in implementing a dedicated magnetic resonance (MR) scanner for radiotherapy (RT) treatment planning using a novel coil setup for brain imaging in treatment position as well as to present developed core protocols with sequences specifically tuned for brain and prostate RT treatment planning. MATERIALS AND METHODS: Our novel setup consists of two large 18-channel flexible coils and a specifically designed wooden mask holder mounted on a flat tabletop overlay, which allows patients to be measured in treatment position with mask immobilization. The signal-to-noise ratio (SNR) of this setup was compared to the vendor-provided flexible coil RT setup and the standard setup for diagnostic radiology. The occurrence of motion artifacts was quantified. To develop magnetic resonance imaging (MRI) protocols, we formulated site- and disease-specific clinical objectives. RESULTS: Our novel setup showed mean SNR of 163 ± 28 anteriorly, 104 ± 23 centrally, and 78 ± 14 posteriorly compared to 84 ± 8 and 102 ± 22 anteriorly, 68 ± 6 and 95 ± 20 centrally, and 56 ± 7 and 119 ± 23 posteriorly for the vendor-provided and diagnostic setup, respectively. All differences were significant (p > 0.05). Image quality of our novel setup was judged suitable for contouring by expert-based assessment. Motion artifacts were found in 8/60 patients in the diagnostic setup, whereas none were found for patients in the RT setup. Site-specific core protocols were designed to minimize distortions while optimizing tissue contrast and 3D resolution according to indication-specific objectives. CONCLUSION: We present a novel setup for high-quality imaging in treatment position that allows use of several immobilization systems enabling MR-only workflows, which could reduce unnecessary dose and registration inaccuracies.

Magnetic resonance imaging for brain stereotactic radiotherapy : A review of requirements and pitfalls.

Due to its superior soft tissue contrast, magnetic resonance imaging (MRI) is essential for many radiotherapy treatment indications. This is especially true for treatment planning in intracranial tumors, where MRI has a long-standing history for target delineation in clinical practice. Despite its routine use, care has to be taken when selecting and acquiring MRI studies for the purpose of radiotherapy treatment planning. Requirements on MRI are particularly demanding for intracranial stereotactic radiotherapy, where accurate imaging has a critical role in treatment success. However, MR images acquired for routine radiological assessment are frequently unsuitable for high-precision stereotactic radiotherapy as the requirements for imaging are significantly different for radiotherapy planning and diagnostic radiology. To assure that optimal imaging is used for treatment planning, the radiation oncologist needs proper knowledge of the most important requirements concerning the use of MRI in brain stereotactic radiotherapy. In the present review, we summarize and discuss the most relevant issues when using MR images for target volume delineation in intracranial stereotactic radiotherapy.

Evaluation of the influence of susceptibility-induced magnetic field distortions on the precision of contouring intracranial organs at risk for stereotactic radiosurgery.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) is a crucial factor in optimal treatment planning for stereotactic radiosurgery. To further the awareness of possible errors in MRI, this work aimed to investigate the magnitude of susceptibility induced MRI distortions for intracranial organs at risk (OARs) and test the effectiveness of actively shimming these distortions. MATERIALS AND METHODS: Distortion maps for 45 exams of 42 patients (18 on a 1.5 T MRI scanner, 27 on a 3 T MRI scanner) were calculated based on a high-bandwidth double-echo gradient echo sequence. The investigated OARs were brainstem, chiasm, eyes, and optic nerves. The influence of active shimming was investigated by comparing unshimmed 1.5 T data with shimmed 3 T data and comparing the results to a model based prediction. RESULTS: The median distortion for the different OARs was found to be between 0.13 and 0.18 mm for 1.5 T and between 0.11 and 0.13 mm for 3 T. The maximum distortion was found to be between 1.3 and 1.7 mm for 1.5 T and between 1.1 and 1.4 mm for 3 T. The variation of values was much higher for 1.5 T than for 3 T across all investigated OARs. Active shimming was found to reduce distortions by a factor of 2.3 to 2.9 compared to the expected values. CONCLUSIONS: Using a safety margin for OARs of 1 mm would have encompassed 99.8% of the distortions. Since distortions are inversely proportional to the readout bandwidth, they can be further reduced by increasing the bandwidth. Additional error sources like gradient nonlinearities need to be addressed separately.

Dose-volume predictors of early esophageal toxicity in non-small cell lung cancer patients treated with accelerated-hyperfractionated radiotherapy.

BACKGROUND AND PURPOSE: Early radiation-induced esophageal toxicity (RIET) is one of the major side effects in patients with non-small cell lung cancer (NSCLC) and can be a reason for treatment interruptions. As the age of patients with NSCLC and corresponding comorbidities continue to increase, primary radiotherapy alone is a commonly used alternative treatment in these cases. The aim of the present study is to compare dosimetric and clinical parameters from the previously reported CHARTWEL trial for their ability to predict esophagitis and investigate potential differences in the accelerated and conventional fractionation arm. MATERIAL AND METHODS: 146 patients of the Dresden cohort of the randomized phase III CHARTWEL trial were included in this post-hoc analysis. Side effects were prospectively scored weekly during the first 8 weeks from start of radiotherapy. To compare both treatment arms, recorded dose-volume parameters were adjusted for the different fractionation schedules. Logistic regression was performed to predict early RIET for the entire study group as well as for the individual treatment arms. Different dosimetric and clinical parameters were tested. RESULTS: Patients receiving the accelerated CHARTWEL schedule experienced earlier and more severe esophagitis (e.g. 20.5% vs. 9.6% ≥grade 2 at week 3, respectively). In contrast, the median time period for recovery of grade 1 esophagitis was significantly longer for patients with conventional fractionation compared to the CHARTWEL group (median [range]: 21 [12-49] days vs. 15 [7-84] days, p = 0.028). In univariable logistic regression none of the dose-volume parameters showed a significant correlation with early RIET grade ≥ 2 in the conventional irradiation group. In contrast, for patients receiving CHARTWEL, the physical dose-volumes parameters V40 and V50; and re-scaled values VEQD2,50 and VEQD2,60 were significant predictors of early RIET grade ≥ 2. Dose-volume parameters remained different between CHARTWEL and conventional fractionation even after biological rescaling. CONCLUSION: Our results show a more dominant dose-volume effect in the CHARTWEL arm compared to conventional fractionation, especially for higher esophageal doses. These findings support the notion that dose-volume parameters for radiation esophagitis determined in a specific and time dependent setting of field arrangements can not be easily transferred to another setting. In clinical practice esophageal volumes receiving 40 Gy or more should be strictly limited in hyperfractionated-accelerated fraction schemes.

Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute.

Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused radiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic radiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was aimed to perform an initial dose-searching study for the combination of these treatment modalities in a preclinical setting. Therapy studies were performed with xenograft mouse models of folate receptor (FR)-positive KB and prostate-specific membrane antigen (PSMA)-positive PC-3 PIP tumors, respectively. PT and TRT using 177Lu-folate and 177Lu-PSMA-617, respectively, were applied either as single treatments or in combination. Monitoring of the mice over nine weeks revealed a similar tumor growth delay after PT and TRT, respectively, when equal tumor doses were delivered either by protons or by ߯-particles, respectively. Combining the methodologies to provide half-dose by either therapy approach resulted in equal (PC-3 PIP tumor model) or even slightly better therapy outcomes (KB tumor model). In separate experiments, preclinical positron emission tomography (PET) was performed to investigate tissue activation after proton irradiation of the tumor. The high-precision radiation delivery of PT was confirmed by the resulting PET images that accurately visualized the irradiated tumor tissue. In this study, the combination of PT and TRT resulted in an additive effect or a trend of synergistic effects, depending on the type of tumor xenograft. This study laid the foundation for future research regarding therapy options in the situation of metastasized solid tumors, where surgery or PT alone are not a solution but may profit from combination with systemic radiation therapy.

The dosimetric effect of residual breath-hold motion in pencil beam scanned proton therapy - An experimental study.

BACKGROUND AND PURPOSE: Motion management in the treatment of lung cancer is necessary to assure highest quality of the delivered radiation therapy. In this study, the breath-hold technique is experimentally investigated for pencil beam scanned (PBS) proton therapy, with respect to the dosimetric effect of residual breath-hold motion. MATERIAL AND METHODS: Three-dimensional (3D)-printed tumours extracted from CT scans of three patients were inserted into a dynamic anthropomorphic breathing phantom. The target was set up to move with the individual patient's tumour motion during breath-hold as previously assessed on fluoroscopy. Target dose was measured with radio-chromic film, and both single field uniform dose (SFUD) and intensity-modulated proton therapy (IMPT) plans were delivered. Experiments were repeated for each patient without any motion, to compute the relative dose deviation between static and breath-hold cases. RESULTS: SFUD plans showed small dose deviations between static and breath-hold cases, as evidenced by the gamma pass rate (3%, 3 mm) of 85% or higher. Dose deviation was more evident for IMPT plans, with gamma pass rate reduced to 50-70%. CONCLUSIONS: The breath-hold technique is robust to residual intra-breath-hold motion for SFUD treatment plans, based on our experimental study. IMPT was less robust with larger detected dose deviations.

Correlation between FMISO-PET based hypoxia in the primary tumour and in lymph node metastases in locally advanced HNSCC patients.

PURPOSE: This secondary analysis of the prospective study on repeat [18F]fluoromisonidazole (FMISO)-PET in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) assessed the correlation of hypoxia in the primary tumour and lymph node metastases (LN) prior to and during primary radiochemotherapy. METHODS: This analysis included forty-five LN-positive HNSCC patients having undergone FMISO-PET/CTs at baseline, and at week 1, 2 and 5 of radiochemotherapy. The quantitative FMISO-PET/CT parameters maximum standardised uptake value (SUVmax, corrected for partial volume effect) and peak tumour-to-background ratio (TBRpeak) were estimated in the primary tumour as well as in index and large LN, respectively. Statistical analysis was performed using the Spearman correlation coefficient ρ. RESULTS: In 15 patients with large LN (FDG-PET positive volume >5 ml), there was a significant correlation between the hypoxia measured in the primary tumour and the large LN at three out of four time-points using the TBRpeak (baseline: ρ = 0.57, p = 0.006; week 2: ρ = 0.64, p = 0.003 and week 5: ρ = 0.68, p = 0.001). For the entire cohort (N = 45) only assessed prior to the treatment, there was a statistically significant, though weak correlation between FMISO-SUVmax of the primary tumour and the index LN (ρ = 0.36, p = 0.015). CONCLUSIONS: We observed a significant correlation between FMISO-based hypoxia in the primary tumour and large lymph node(s) in advanced stage HNSCC patients. However, since most patients only had relatively small hypoxic lymph node metastases, a comprehensive assessment of the primary tumour and lymph node hypoxia is essential.

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

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.

Feasibility of Pencil Beam Scanned Intensity Modulated Proton Therapy in Breath-hold for Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: We evaluated the feasibility of treating patients with locally advanced non-small cell lung cancer (NSCLC) with pencil beam scanned intensity modulated proton therapy (IMPT) in breath-hold. METHODS AND MATERIALS: Fifteen NSCLC patients who had previously received 66 Gy in 33 fractions with image guided photon radiation therapy were included in the present simulation study. In addition to a planning breath-hold computed tomography (CT) scan before the treatment start, a median of 6 (range 3-9) breath-hold CT scans per patient were acquired prospectively throughout the radiation therapy course. Three-field IMPT plans were constructed using the planning breath-hold CT scan, and the four-dimensional dose distributions were simulated, with consideration of both patient intra- and interfraction motion, in addition to dynamic treatment delivery. RESULTS: The median clinical target volume receiving 95% of the prescribed dose was 99.8% and 99.7% for the planned and simulated dose distributions, respectively. For 3 patients (20%), the dose degradation was >5%, and plan adjustment was needed. Dose degradation correlated significantly with the change in water-equivalent path lengths (P<.01) in terms of the percentage of voxels with 3-mm or more undershoot on repeat CT scans. The dose to the organs at risk was similar for the planned and simulated dose distributions. Three or fewer breath-holds per field would be required for 12 of the 15 patients, which was clinically feasible. CONCLUSIONS: For 9 of 15 NSCLC patients, IMPT in breath-hold was both dosimetrically robust and feasible to deliver regarding the treatment time. Three patients would have required plan adaption to meet the dosimetric criteria. The change in water-equivalent path length is an indicator of plan robustness and should be considered for the selection of patients for whom the plan would require adaptation.

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.

Advanced treatment planning using direct 4D optimisation for pencil-beam scanned particle therapy.

We report on development of a new four-dimensional (4D) optimisation approach for scanned proton beams, which incorporates both irregular motion patterns and the delivery dynamics of the treatment machine into the plan optimiser. Furthermore, we assess the effectiveness of this technique to reduce dose to critical structures in proximity to moving targets, while maintaining effective target dose homogeneity and coverage. The proposed approach has been tested using both a simulated phantom and a clinical liver cancer case, and allows for realistic 4D calculations and optimisation using irregular breathing patterns extracted from e.g. 4DCT-MRI (4D computed tomography-magnetic resonance imaging). 4D dose distributions resulting from our 4D optimisation can achieve almost the same quality as static plans, independent of the studied geometry/anatomy or selected motion (regular and irregular). Additionally, current implementation of the 4D optimisation approach requires less than 3 min to find the solution for a single field planned on 4DCT of a liver cancer patient. Although 4D optimisation allows for realistic calculations using irregular breathing patterns, it is very sensitive to variations from the planned motion. Based on a sensitivity analysis, target dose homogeneity comparable to static plans (D5-D95 <5%) has been found only for differences in amplitude of up to 1 mm, for changes in respiratory phase <200 ms and for changes in the breathing period of <20 ms in comparison to the motions used during optimisation. As such, methods to robustly deliver 4D optimised plans employing 4D intensity-modulated delivery are discussed.

Impact of beam angle choice on pencil beam scanning breath-hold proton therapy for lung lesions.

INTRODUCTION: The breath-hold technique inter alia has been suggested to mitigate the detrimental effect of motion on pencil beam scanned (PBS) proton therapy dose distributions. The aim of this study was to evaluate the robustness of incident proton beam angles to day-to-day anatomical variations in breath-hold. MATERIALS AND METHODS: Single field PBS plans at five degrees increments in the transversal plane were made and water-equivalent path lengths (WEPLs) were derived on the planning breath-hold CT (BHCT) for 30 patients diagnosed with locally-advanced non-small cell lung cancer (NSCLC), early stage NSCLC or lung metastasis. Our treatment planning system was subsequently used to recalculate the plans and derive WEPL on a BHCT scan acquired at the end of the treatment. Changes to the V95%, D95 and mean target dose were evaluated. RESULTS: The difference in WEPL as a function of the beam angle was highly patient specific, with a median of 3.3 mm (range: 0.0-41.1 mm). Slightly larger WEPL differences were located around the lateral or lateral anterior/posterior beam angles. Linear models revealed that changes in dose were associated to the changes in WEPL and the tumor baseline shift (p < 0.05). CONCLUSIONS: WEPL changes and tumor baseline shift can serve as reasonable surrogates for dosimetric uncertainty of the target coverage and are well-suited for routine evaluation of plan robustness. The two lateral beam angles are not recommended to use for PBS proton therapy of lung cancer patients treated in breath-hold, due to the poor robustness for several of the patients evaluated.

Monitoring of breathing motion in image-guided PBS proton therapy: comparative analysis of optical and electromagnetic technologies.

BACKGROUND: Motion monitoring is essential when treating non-static tumours with pencil beam scanned protons. 4D medical imaging typically relies on the detected body surface displacement, considered as a surrogate of the patient's anatomical changes, a concept similarly applied by most motion mitigation techniques. In this study, we investigate benefits and pitfalls of optical and electromagnetic tracking, key technologies for non-invasive surface motion monitoring, in the specific environment of image-guided, gantry-based proton therapy. METHODS: Polaris SPECTRA optical tracking system and the Aurora V3 electromagnetic tracking system from Northern Digital Inc. (NDI, Waterloo, CA) have been compared both technically, by measuring tracking errors and system latencies under laboratory conditions, and clinically, by assessing their practicalities and sensitivities when used with imaging devices and PBS treatment gantries. Additionally, we investigated the impact of using different surrogate signals, from different systems, on the reconstructed 4D CT images. RESULTS: Even though in controlled laboratory conditions both technologies allow for the localization of static fiducials with sub-millimetre jitter and low latency (31.6 ± 1 msec worst case), significant dynamic and environmental distortions limit the potential of the electromagnetic approach in a clinical setting. The measurement error in case of close proximity to a CT scanner is up to 10.5 mm and precludes its use for the monitoring of respiratory motion during 4DCT acquisitions. Similarly, the motion of the treatment gantry distorts up to 22 mm the tracking result. CONCLUSIONS: Despite the line of sight requirement, the optical solution offers the best potential, being the most robust against environmental factors and providing the highest spatial accuracy. The significant difference in the temporal location of the reconstructed phase points is used to speculate on the need to apply the same monitoring system for imaging and treatment to ensure the consistency of detected phases.

Liquid fiducial marker applicability in proton therapy of locally advanced lung cancer.

BACKGROUND AND PURPOSE: We investigated the clinical applicability of a novel liquid fiducial marker (LFM) for image-guided pencil beam scanned (PBS) proton therapy (PBSPT) of locally advanced lung cancer (LALC). MATERIALS AND METHODS: The relative proton stopping power (RSP) of the LFM was calculated and measured. Dose perturbations of the LFM and three solid markers, in a phantom, were measured. PBSPT treatment planning on computer tomography scans of five patients with LALC with the LFM implanted was performed with 1-3 fields. RESULTS: The RSP was experimentally determined to be 1.164 for the LFM. Phantom measurements revealed a maximum relative deviation in dose of 4.8% for the LFM in the spread-out Bragg Peak, compared to 12-67% for the solid markers. Using the experimentally determined RSP, the maximum proton range error introduced by the LFM is about 1mm. If the marker was displaced at PBSPT, the maximum dosimetric error was limited to 2 percentage points for 3-field plans. CONCLUSION: The dose perturbations introduced by the LFM were considerably smaller than the solid markers investigated. The RSP of the fiducial marker should be corrected in the treatment planning system to avoid errors. The investigated LFM introduced clinically acceptable dose perturbations for image-guided PBSPT of LALC.

Respiratory motion-management in stereotactic body radiation therapy for lung cancer - A dosimetric comparison in an anthropomorphic lung phantom (LuCa).

BACKGROUND AND PURPOSE: The objective of this study was to compare the latest respiratory motion-management strategies, namely the internal-target-volume (ITV) concept, the mid-ventilation (MidV) principle, respiratory gating and dynamic couch tracking. MATERIALS AND METHODS: An anthropomorphic, deformable and dynamic lung phantom was used for the dosimetric validation of these techniques. Stereotactic treatments were adapted to match the techniques and five distinct respiration patterns, and delivered to the phantom while radiographic film measurements were taken inside the tumor. To report on tumor coverage, these dose distributions were used to calculate mean doses (Dmean), changes in homogeneity indices (ΔH2-98), gamma agreement, and areas covered by the planned minimum dose (A>Dmin). RESULTS: All techniques achieved good tumor coverage (A>Dmin>99.0%) and minor changes in Dmean (±3.2%). Gating and tracking strategies showed superior results in gamma agreement and ΔH2-98 compared to ITV and MidV concepts, which seem to be more influenced by the interplay and the gradient effect. For lung, heart and spinal cord, significant dose differences between the four techniques were found (p<0.05), with lowest doses for gating and tracking strategies. CONCLUSION: Active motion-management techniques, such as gating or tracking, showed superior tumor dose coverage and better organ dose sparing than the passive techniques based on tumor margins.

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.

Four-Dimensional Dose Reconstruction for Scanned Proton Therapy Using Liver 4DCT-MRI.

PURPOSE: Four-dimensional computed tomography-magnetic resonance imaging (4DCT-MRI) is an image-processing technique for simulating many 4DCT data sets from a static reference CT and motions extracted from 4DMRI studies performed using either volunteers or patients. In this work, different motion extraction approaches were tested using 6 liver cases, and a detailed comparison between 4DCT-MRI and 4DCT was performed. METHODS AND MATERIALS: 4DCT-MRI has been generated using 2 approaches. The first approach used motion extracted from 4DMRI as being "most similar" to that of 4DCT from the same patient (subject-specific), and the second approach used the most similar motion obtained from a motion library derived from 4DMRI liver studies of 13 healthy volunteers (population-based). The resulting 4DCT-MRI and 4DCTs were compared using scanned proton 4D dose calculations (4DDC). RESULTS: Dosimetric analysis showed that 93% ± 8% of points inside the clinical target volume (CTV) agreed between 4DCT and subject-specific 4DCT-MRI (gamma analysis: 3%/3 mm). The population-based approach however showed lower dosimetric agreement with only 79% ± 14% points in the CTV reaching the 3%/3 mm criteria. CONCLUSIONS: 4D CT-MRI extends the capabilities of motion modeling for dose calculations by accounting for realistic and variable motion patterns, which can be directly employed in clinical research studies. We have found that the subject-specific liver modeling appears more accurate than the population-based approach. The former is particularly interesting for clinical applications, such as improved target delineation and 4D dose reconstruction for patient-specific QA to allow for inter- and/or intra-fractional plan corrections.

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.

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

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.