<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04457102</url>
  </required_header>
  <id_info>
    <org_study_id>2020/03FEV/065</org_study_id>
    <nct_id>NCT04457102</nct_id>
  </id_info>
  <brief_title>Mechanically-Assisted and Non-Invasive Ventilation for Breathing-related Tumor Motion Mitigation.</brief_title>
  <acronym>MANIV</acronym>
  <official_title>Implementation and Clinical Validation of Mechanically-Assisted and Non-Invasive Ventilation (MANIV) in Radiotherapy for Breathing-related Tumor Motion Management.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cliniques universitaires Saint-Luc- Université Catholique de Louvain</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cliniques universitaires Saint-Luc- Université Catholique de Louvain</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Breathing motion still remains a major issue that jeopardizes the accuracy of photon- and&#xD;
      proton-therapy for thoracic and upper-abdominal tumors, which represent up to 40% of curative&#xD;
      radiotherapy treatments. Existing motion management strategies are either simple and costless&#xD;
      but lead to futile irradiation of healthy tissues (safety margins), or complex to implement&#xD;
      and expensive, limiting their availability in clinical routine (gating, deep-inspiration&#xD;
      breath-hold - DIBH, real-time tracking). In addition, the accuracy and efficiency of all&#xD;
      these techniques critically depend on tumor motion/position reproducibility over treatment&#xD;
      time, which is often degraded by variations of the spontaneous breathing or voluntary apnea.&#xD;
      Finally, these techniques are not easily transferrable to proton therapy (PT) in the presence&#xD;
      of proton range uncertainties in moving anatomy.&#xD;
&#xD;
      Therefore, we propose an innovative workaround to overcome these complex issues, namely,&#xD;
      Mechanically-Assisted and Non-Invasive Ventilation (MANIV). By taking control of the&#xD;
      patient's breathing, we previously demonstrated that MANIV can safely regularize and even&#xD;
      reduce tumor motion using a volume-controlled ventilation mode (VC), while a slow ventilation&#xD;
      mode (SL) can induce repeated DIBH during which the tumor motion is nearly suppressed.&#xD;
      Although promising, we have to go a step further into the prospective clinical validation of&#xD;
      MANIV applied to existing motion management techniques.&#xD;
&#xD;
      A. Preclinical phase:&#xD;
&#xD;
        1. Clinical implementation of MANIV: development of technical solutions to integrate MANIV&#xD;
           at each stage of a patient's clinical workflow in our radiotherapy department.&#xD;
&#xD;
        2. In-house validation and optimization of experimental mathematical models to compute the&#xD;
           trajectory and amplitude of residual tumor motion during treatment delivery.&#xD;
&#xD;
      B. Clinical phase:&#xD;
&#xD;
        1. Optimization of Respiratory Gating by reproducing repeated and stable DIBHs to fix the&#xD;
           tumor motion for radiotherapy treatment of lung, liver and breast tumors.&#xD;
&#xD;
        2. Optimization of Tracking procedures by regularizing the breathing and tumor motion with&#xD;
           VC mode to reduce the treatment duration for real-time lung and liver tumors tracking on&#xD;
           Accuray Cyberknife® robotic mounted LINAC.&#xD;
&#xD;
        3. In silico delivred dose assessment of MANIV-optimized Respiratory Gating by Pencil Beam&#xD;
           Scanning Proton Therapy (PBS-PT).&#xD;
&#xD;
      At the end of this project, we will provide recommendations for the clinical implementation&#xD;
      of a wide panel of advanced motion mitigation techniques, which would contribute to a major&#xD;
      step forward in the management of breathing motion in both photon and proton-therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Radiotherapy of mobile tumors faces many challenges due to breathing-related geometrical&#xD;
      uncertainties. Breathing amplitude and frequency may deeply and unexpectedly vary from cycle&#xD;
      to cycle, during a treatment fraction (intra-fraction variation) or between fractions&#xD;
      (inter-fraction variation) [1]. In Protontherapy (PT), these uncertainties are even worsened&#xD;
      by the proton range variations within the traversed moving tissues and the interplay effect&#xD;
      between the tumor and spot scanning beam motions. These effects can unpredictively and&#xD;
      severely distort dose distribution, and still limit the current indications of PT for&#xD;
      thoracic/upper-abdomen cancers [2, 3]. Therefore, several motion mitigation strategies have&#xD;
      been developed:&#xD;
&#xD;
        -  Margin Strategy: this approach consists in calculating safety margins that encompass&#xD;
           motion-related uncertainties computed from a prior planning 4D-CT scan. Although simple&#xD;
           to implement, it inevitably results in futile dose exposure to organs at risk [4].&#xD;
&#xD;
        -  Gating Strategy: respiratory gating consists in delivering the beam within a time-window&#xD;
           of the breathing cycle, at the end-expiratory or inspiratory plateau, when the tumor is&#xD;
           in a predefined stable position. It prevents potentially harmful irradiation of healthy&#xD;
           tissues by reducing safety margins [4]. During Deep Inspiration Breath Hold (DIBH), the&#xD;
           patient is asked to hold apneas after deep inspirations to prolong the gating windows&#xD;
           and the time efficiency of the gating procedure. DIBH has become a standard of care for&#xD;
           left breast radiotherapy. Indeed, in addition of freezing the tumor motion, it moves&#xD;
           away the heart from the breast and inflates the lungs, allowing thus to reduce the dose&#xD;
           to these critical organs at risk [5]. However, for all tumor sites ( breast, lung,&#xD;
           liver), current beam delivery times typically entail several successive spontaneous BH&#xD;
           to complete treatment, hence require complex management with onboard imaging to monitor&#xD;
           the target position [6]. Moreover, repeating spontaneous DIBH requires a good patient's&#xD;
           compliance and comprehension, which may be a barrier for some patients, and may degrade&#xD;
           the accuracy of the gating procedure. Various techniques have been investigated to&#xD;
           improve the tumor position reproducibility over successive BH or to increase BH duration&#xD;
           to facilitate dose delivery [7,8,9]. However, the patient invariably remains actor of&#xD;
           his breathing with subsequent unpredictive tumor position variations from BH to BH. As a&#xD;
           consequence, the accuracy could suffer from residual motion and unpredictable changes&#xD;
           during spontaneous breath-holds.&#xD;
&#xD;
        -  Tracking Strategy: this approach relies on motion prediction models derived patient's&#xD;
           real-time breathing pattern, allowing for the synchronization of the tumor motion with&#xD;
           the beam motion. Accuray Cyberknife® is a LINAC mounted on a robotic arm designed for&#xD;
           real-time tumor tracking. A correlation model is built between external motion&#xD;
           continuously tracked by LEDs placed on the patient and internal tumor position, tracked&#xD;
           periodically by orthogonal x-rays imagers. The correlation model is updated whenever&#xD;
           deviations occur due to changes of the breathing pattern [10]. Tracking allows thus to&#xD;
           significantly reduce the safety margins and to adapt continuously the treatment delivery&#xD;
           to the breathing pattern [4]. However, the long delivery time of a single fraction, from&#xD;
           60 to 90 minutes [11], limits its current use in clinical practice. Again, erratic and&#xD;
           non-reproducible breathing may degrade the accuracy of tracking and will require&#xD;
           frequent updates of the motion correlation model, at the expense of even longer&#xD;
           treatment time and discomfort for the patient.&#xD;
&#xD;
      Until now, none of the current strategy provides an entirely satisfactory solution for motion&#xD;
      management. The more accurate a technique is, the less efficient it is (treatment time,&#xD;
      feasibility, ease of clinical implementation), and vice-versa. By taking control of the&#xD;
      patient breathing, MANIV could solve this complex problem. Parkes et al. showed first that&#xD;
      MANIV can safely impose a regular breathing pattern on conscious and unsedated patients [12],&#xD;
      and could mitigate respiratory motion [13, 14]. Our group has further investigated these&#xD;
      ventilation techniques on healthy volunteers [15] and patients [16] to broaden their&#xD;
      applicability to radiotherapy of moving tumors. Two ventilation modes appear to be of&#xD;
      particular interest for radiotherapy :&#xD;
&#xD;
        -  The Slow Controlled ventilation mode (SL) is a bi-level pressure mode of the mechanical&#xD;
           ventilator that induces reproducible and repeated DIBH without active patient&#xD;
           participation. This ventilation mode therefore offers a way to improve the efficiency&#xD;
           and accuracy of respiratory gating. Indeed, a good physical condition of the patient,&#xD;
           his compliance or his understanding of the instructions would no longer be necessary&#xD;
           prerequisites for the feasibility of the treatment. Thus, by relieving the patient of&#xD;
           his breathing control, MANIV would overcome the limitations of spontaneous DIBH and&#xD;
           would allow a larger number of patients to benefit from this technique. Moreover, the&#xD;
           intra- and inter-fraction baseline shift (= mean position variation over time) are&#xD;
           reduced with MANIV compared to voluntary DIBH [15] and should improve the accuracy of&#xD;
           the gating procedure. MANIV will thus facilitate both onboard imaging procedure for&#xD;
           patient positioning and the beam delivery accuracy. In the context of proton therapy,&#xD;
           freezing the tumor motion thanks to SL mode would allow to treat thoracic and abdominal&#xD;
           tumors by drastically reducing the motion-related geometrical uncertainties that have&#xD;
           been prohibitive until now to ensure satisfactory robustness of the planned dose&#xD;
           distribution.&#xD;
&#xD;
        -  The Volume Controlled ventilation mode (VC) constraints both breathing rate and tidal&#xD;
           volume measured from the patient's spontaneous breathing parameters, and imposes a&#xD;
           completely regular breathing pattern without increasing the tumor baseline shift&#xD;
           [15,16]. Stabilization of the respiratory pattern over time would be beneficial for&#xD;
           tracking strategy. We can hypothesize that the regular breathing and tumor motions&#xD;
           imposed by MANIV would reduce the number of model updates and the overall treatment&#xD;
           duration, with a substantial gain in efficiency of the technique. To a lesser extent,&#xD;
           the accuracy of the technique would also be improved [17].&#xD;
&#xD;
      In summary, our group has already demonstrated that MANIV was feasible and safe on small&#xD;
      cohorts of volunteers and patients, and significantly improved regularity of&#xD;
      breathing-related motion or BH monitored by real-time dynamic MRI [15,16]. Based on these&#xD;
      very encouraging pre-clinical results, MANIV might thus considerably simplify and improve all&#xD;
      motion management strategies in both photon- and proton therapies. However, further clinical&#xD;
      investigations are still required in real treatment conditions to validate its use for&#xD;
      clinical routine. These include the clinical implementation of the ventilator in a LINAC&#xD;
      environment, and the quantification of the added value of MANIV for the above-mentioned&#xD;
      mitigation techniques.&#xD;
&#xD;
      Research project We plan first to implement MANIV in the patient workflow and to validate and&#xD;
      optimize our onboard imaging procedure to quantify residual motion or motion regularity.&#xD;
      Then, we will conduct 4 clinical studies, each investigating the added value of MANIV for a&#xD;
      specific motion management strategy.&#xD;
&#xD;
      A) Preclinical phase :&#xD;
&#xD;
      MANIV has been interfaced with the control room of our LINACs to monitor the MANIV breathing&#xD;
      parameters. Intra-fraction motion will be monitored during gating treatments using Cone-Beam&#xD;
      CT (CBCT). Computing motion from these devices will require the use of experimental&#xD;
      mathematical models to infer the three-dimensional trajectory of a tumor from its&#xD;
      two-dimensional X-rays projections. Five models have been reported in the literature&#xD;
      [18,19,20,21,22]. The one of Poulsen et al [22] based on a probabilistic approach is the most&#xD;
      accurate with a submillimetric residual error [23]. We have already validated this method in&#xD;
      the environnement our treatment machines with a dynamic thorax phantom (model 008A CIRS®),&#xD;
      and we are now able to analyze intra-fraction motion from imaging data of patients treated on&#xD;
      our LINACs.&#xD;
&#xD;
      B) Clinical phase:&#xD;
&#xD;
      For all clinical studies, subjective and objective patient's tolerance will be monitored&#xD;
      during MANIV with comfort questionnaires (Likert scales and visual analogue scale) and vital&#xD;
      parameters (Heartbeat Rate, SpO2, etCO2). Statistical power analysis were performed using the&#xD;
      PASS 14.0.7 statistical software.&#xD;
&#xD;
        1. Improving respiratory gating with MANIV-induced DIBH for liver and lung cancers RT:&#xD;
&#xD;
             -  Design: Non-comparative prospective interventional study.&#xD;
&#xD;
             -  Population: Patients with primary or secondary hepatic or pulmonary neoplasia&#xD;
                eligible for radiotherapy.&#xD;
&#xD;
             -  Method: Irradiation will take place during DIBH induced by the MANIV (Bellavista&#xD;
                1000, IMTMedical®) with SL mode. Oxygen will be added (FiO2 60%) to safely and&#xD;
                easily prolong the DIBH duration up to 40-50 seconds to allow the complete delivery&#xD;
                of a treatment beam [13]. Prior to treatment, a radio-opaque fiducial will be&#xD;
                implanted in the tumor by an interventional radiologist, to facilitate the tumor&#xD;
                position monitoring from onboard imaging. Residual tumor baseline shift and motion&#xD;
                will thus be measured during beam delivery, and used to recompute the optimal&#xD;
                safety margins that ensure an adequate dose coverage of at least 90% of tumors,&#xD;
                according to literature recommendations [24]. We will also compare these safety&#xD;
                margins computed under MANIV condition with those routinely applied in&#xD;
                free-breathing condition (from a matched retrospective cohort) to estimate the gain&#xD;
                in terms of margin reduction.&#xD;
&#xD;
             -  Primary outcome: Feasibility of treatment completion with mechanical-ventilation.&#xD;
&#xD;
             -  Secondary outcome: a) Proportion of tumors receiving the prescribed dose. b)&#xD;
                Recalculation of safety margins adapted to the MANIV in SL mode and margin&#xD;
                reduction compared to conventional free breathing RT.&#xD;
&#xD;
             -  Statistical power analysis : Considering a poor and good feasibility tresholds of&#xD;
                70 % and 95 %, respectively and assuming a drop-out of 10 %, a total of 16 patients&#xD;
                are needed ( alpha level of 0,05 and beta level of 0,8 ).&#xD;
&#xD;
        2. Improving respiratory gating with MANIV-Induced DIBH for breast RT:&#xD;
&#xD;
             -  Design: Randomized controlled trial with equiprobable randomization by block of 4&#xD;
                in 2 arms: the interventional arm will be treated with MANIV-induced DIBH and the&#xD;
                control arm treated in spontaneous DIBH&#xD;
&#xD;
             -  Population: Patients with left breast neoplasia eligible for treatment by&#xD;
                radiotherapy.&#xD;
&#xD;
             -  Method: Patients in the interventional arm will be treated under the same&#xD;
                conditions as described above. Optical surface imaging (VisionRT® - Identify®) will&#xD;
                be used to monitor in real-time the breast position during beam delivery. Based on&#xD;
                this information, the mean breast displacement will be compared between the two&#xD;
                arms. The planned dose to the organs at risk (heart, lung) will also be computed&#xD;
                and compared between both arms. The conversion ratio from the DIBH technique to a&#xD;
                free breathing treatment will be analyzed in each arm as a surrogate of the DIBH&#xD;
                strategy efficiency. The treatment will indeed be performed in free breathing when&#xD;
                the patient will not be able to hold a DIBH for a long enough time for the delivery&#xD;
                of the treatment.&#xD;
&#xD;
             -  Primary outcome: mean displacements of the mammary gland during treatment.&#xD;
&#xD;
             -  Secondary outcomes: a) Planned dose to organs at risk (especially heart and lung)&#xD;
                b) Proportion of conversion to free-breath in each arm.&#xD;
&#xD;
             -  Statistical power analysis : 27 patients should be included in each arm to rule an&#xD;
                additional deviation of 1 mm of the mammary gland during treatment (non-inferiority&#xD;
                margin of 1 mm) using an independent 2 samples proportion t-test (one-tailed) to&#xD;
                reach a statistical power of 95 % (alpha error = 2,5 %).&#xD;
&#xD;
        3. Improving respiratory real-time tracking by VC mode:&#xD;
&#xD;
             -  Design: Non-comparative prospective interventional study.&#xD;
&#xD;
             -  Population: Patients with primary or secondary hepatic neoplasia eligible for a&#xD;
                radiotherapy treatment.&#xD;
&#xD;
             -  Method: Patients will be ventilated by VC mode during their treatment. For each&#xD;
                fraction, the treatment time, the number of reconstructions of the tracking model&#xD;
                and the correlation errors of the model will be collected. The same information&#xD;
                will be extracted from a matched retrospective cohort treated by tracking in&#xD;
                spontaneous breathing.&#xD;
&#xD;
             -  Primary outcome: Mean duration of a fraction.&#xD;
&#xD;
             -  Secondary outcomes: a) Correlation errors of the model, b) accuracy of the tracking&#xD;
&#xD;
             -  Statistical power analysis : 20 patients should be included in both cohorts (the&#xD;
                prospective and retrospective one) to demonstrate a reduction of the mean treatment&#xD;
                time (effect size = 0.6) with an independent 2 samples t-test (one tailed) to reach&#xD;
                a statistical power of 80 % (apha error = 5%).&#xD;
&#xD;
        4. Mechanically-induced breath-holds for gated PBS-PT:&#xD;
&#xD;
             -  Design: Non-comparative observational prospective study.&#xD;
&#xD;
             -  Population: Patients included in study n°1&#xD;
&#xD;
             -  Method: data on tumor position and its residual motion from patients included in&#xD;
                the study n°1 will be used to compute the planned and in silico delivered dose&#xD;
                distribution with PBS PT. The MIRO lab (UCL-IREC ) has developed comprehensive&#xD;
                tools for simulating treatment delivery on patients CT images using the Monte Carlo&#xD;
                dose engine MCsquare [25], coupled with log-file acquisitions [26]. In this way, we&#xD;
                will be able to validate our approach in silico in collaboration with IBA, as a&#xD;
                first step before conducting prospective trials for the clinical validation of this&#xD;
                approach.&#xD;
&#xD;
             -  Primary outcome: dose delivered at 95, 98 and 100% of the volume of each tumor.&#xD;
&#xD;
             -  Statistical power analysis : not applicable. Patients from study n°1 (Improving&#xD;
                respiratory gating by SL mode) will be included.&#xD;
&#xD;
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                     https://doi.org/10.1016/j.ijrobp.2008.07.037&#xD;
&#xD;
                 23. Montanaro, T., Nguyen, D. T., Keall, P. J., Booth, J., Caillet, V., Eade, T.,&#xD;
                     … Shieh, C.-C. (2018). A comparison of gantry-mounted x-ray-based real-time&#xD;
                     target tracking methods. Medical Physics, 45(3), 1222 1232.&#xD;
                     https://doi.org/10.1002/mp.12765&#xD;
&#xD;
                 24. van Herk, M., Remeijer, P., Rasch, C., &amp; Lebesque, J. V. (2000). The&#xD;
                     probability of correct target dosage: dose-population histograms for deriving&#xD;
                     treatment margins in radiotherapy. International Journal of Radiation&#xD;
                     Oncology*Biology*Physics, 47(4), 1121 1135.&#xD;
                     https://doi.org/10.1016/s0360-3016(00)00518-6&#xD;
&#xD;
                 25. Souris, K., Lee, J. A., &amp; Sterpin, E. (2016). Fast multipurpose Monte Carlo&#xD;
                     simulation for proton therapy using multi- and many-core CPU architectures.&#xD;
                     Medical Physics, 43(4), 1700 1712. https://doi.org/10.1118/1.4943377&#xD;
&#xD;
                 26. Toscano, S., Souris, K., Gomà, C., Barragán-Montero, A., Puydupin, S.,&#xD;
                     Stappen, F. V., … Sterpin, E. (2019). Impact of machine log-files&#xD;
                     uncertainties on the quality assurance of proton pencil beam scanning&#xD;
                     treatment delivery. Physics in Medicine &amp; Biology, 64(9), 095021.&#xD;
                     https://doi.org/10.1088/1361-6560/ab120c&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 3, 2020</start_date>
  <completion_date type="Anticipated">September 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2024</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Multicentric prospective interventional or retrospective observational study depending on the sub-part considered. It is segmented into 5 sub-parts each investigating the interest of MANIV for a specific motion management technique.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Validation of MANIV-optimized Gating strategy for breast tumors</measure>
    <time_frame>through study completion, an average of 3 weeks</time_frame>
    <description>mean breast gland 3D displacements during treatment delivery.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Validation of MANIV-optimized Gating strategy for lung and liver tumors</measure>
    <time_frame>through study completion, an average of 2 weeks</time_frame>
    <description>Proportion of patients successfully treated with MANIV</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Validation of MANIV-optimized Tracking strategy</measure>
    <time_frame>through study completion, an average of 2 weeks</time_frame>
    <description>Average time required to deliver a fraction</description>
  </primary_outcome>
  <primary_outcome>
    <measure>In silico evaluation of viability with treatment by protontherapy in SL mode</measure>
    <time_frame>through study completion, an average of 2 weeks</time_frame>
    <description>% of CTV volume receiving at least a given dose level by patient</description>
  </primary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Anticipated">241</enrollment>
  <condition>Optimization of Motion Mitigation Strategies by Mechanically-Assisted Non-Invasive Ventilation</condition>
  <arm_group>
    <arm_group_label>Arm N°1 - Standard treatment-Breast DIBH</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will be treated during spontaneous breath hold wich is considered as the gold-standard radiotherapy treatment for left breast cancer.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm N°2 - Interventional -Breast MANIV DIBH</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Irradiation will take place during DIBH induced by MANIV (Bellavista 1000, IMTMedical®) with SL mode. Oxygen will be added (FiO2 60%) to safely and easily prolong the DIBH duration up to 30 seconds to allow the complete delivery of a treatment beam.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm N°3 - Interventional -Liver/Lung MANIV DIBH</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Irradiation will take place during DIBH induced by the MANIV (Bellavista 1000, IMTMedical®) with SL mode. Oxygen will be added (FiO2 60%) to safely and easily prolong the DIBH duration up to 30 seconds to allow the complete delivery of a treatment beam [13]. Prior to treatment, a radio-opaque fiducial will be implanted in the tumor by an interventional radiologist, to facilitate the tumor position monitoring from onboard imaging. Residual tumor baseline shift and motion will thus be measured during beam delivery, and used to recompute the optimal safety margins that ensure an adequate dose coverage of at least 90% of tumors, according to literature recommendations [24]. We will also compare these safety margins computed under MANIV condition with those routinely applied in free-breathing condition to estimate the gain in terms of margin reduction.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm N°4 - Interventional -Liver/Lung MANIV VC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be ventilated by VC mode during their treatment. For each fraction, the treatment time, the number of reconstructions of the tracking model and the correlation errors of the model will be collected. The same information will be extracted from a matched retrospective cohort treated by tracking in spontaneous breathing.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm N°5 -Liver/Lung MANIV DIBH for PT</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Data on tumor position and its residual motion from patients included in the arm n°3 will be used to compute the planned and in silico delivered dose distribution with PBS PT. The MIRO lab (UCLouvain - IREC) has developed comprehensive tools for simulating treatment delivery on patients CT images using the Monte Carlo dose engine MCsquare [25], coupled with log-file acquisitions [26]. In this way, we will be able to validate our approach in silico in collaboration with IBA, as a first step before conducting prospective trials for the clinical validation of this approach.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>MANIV</intervention_name>
    <description>mechanical ventilator (Bellavista 1000, IMTmedical) will be used on Varian® Halcyon LINAC and Infinity Elekta® linac</description>
    <arm_group_label>Arm N°2 - Interventional -Breast MANIV DIBH</arm_group_label>
    <arm_group_label>Arm N°3 - Interventional -Liver/Lung MANIV DIBH</arm_group_label>
    <arm_group_label>Arm N°4 - Interventional -Liver/Lung MANIV VC</arm_group_label>
    <arm_group_label>Arm N°5 -Liver/Lung MANIV DIBH for PT</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Spontaneous DIBH</intervention_name>
    <description>performed on Varian® Halcyon LINAC and Infinity Elekta® linac</description>
    <arm_group_label>Arm N°1 - Standard treatment-Breast DIBH</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  Inclusion Criteria:&#xD;
&#xD;
               1. Validation of the MANIV-optimized gating strategy for breasrt tumors :&#xD;
&#xD;
                  Patients with left breast tumors eligible for radiation therapy with breath hold&#xD;
                  technique.&#xD;
&#xD;
               2. Validation of the MANIV optimized Gating strategy for lung/liver tumors:&#xD;
&#xD;
                  Patients with lung (primary or secondary) or liver (primary or secondary) tumors&#xD;
                  eligible for stereotactic radiation therapy.&#xD;
&#xD;
               3. Validation of the MANIV-optimized Tracking strategy for liver tumors:&#xD;
&#xD;
                  Part 1: Patients with hepatic neoplasia (primary or secondary) eligible for&#xD;
                  stereotactic radiation therapy on the Cyberknife® of the Oscar Lambret center in&#xD;
                  Lille (France)..&#xD;
&#xD;
                  Part 2: Patients with hepatic neoplasia (primary or secondary) treated by&#xD;
                  respiratory tracking on the Cyberknife® of the Oscar Lambret center in Lille&#xD;
                  (France).&#xD;
&#xD;
             4 - Evaluation of a proton therapy treatment delivered in silico to mobile tumors with&#xD;
             MANIV in DIBH mode : Patients included in the study on the optimization of the Gating&#xD;
             strategy.&#xD;
&#xD;
          -  Exclusion Criteria:&#xD;
&#xD;
               -  history of spontaneous pneumothorax&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Geneviève Van Ooteghem, MD,PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Cliniques Universitaires Saint-Luc, Brussels, Belgium</affiliation>
  </overall_official>
  <overall_official>
    <last_name>David Pasquier, MD,PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Centre Oscar Lambret, Lille, France</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Xavier Geets, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cliniques Universitaires Saint-Luc, Brussels, Belgium</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Loïc Vander Veken, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Cliniques Universitaires Saint-Luc,Brussels, Belgium</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cliniques Universitaires Saint-Luc</name>
      <address>
        <city>Woluwe-Saint-Lambert</city>
        <state>Bruxelles</state>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>June 25, 2020</study_first_submitted>
  <study_first_submitted_qc>June 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 7, 2020</study_first_posted>
  <last_update_submitted>May 30, 2023</last_update_submitted>
  <last_update_submitted_qc>May 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04457102
org study id: 2020/03FEV/065
nct id: NCT04457102
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Breathing motion still remains a major issue that jeopardizes the accuracy of photon- and
      proton-therapy for thoracic and upper-abdominal tumors, which represent up to 40% of curative
      radiotherapy treatments. Existing motion management strategies are either simple and costless
      but lead to futile irradiation of healthy tissues (safety margins), or complex to implement
      and expensive, limiting their availability in clinical routine (gating, deep-inspiration
      breath-hold - DIBH, real-time tracking). In addition, the accuracy and efficiency of all
      these techniques critically depend on tumor motion/position reproducibility over treatment
      time, which is often degraded by variations of the spontaneous breathing or voluntary apnea.
      Finally, these techniques are not easily transferrable to proton therapy (PT) in the presence
      of proton range uncertainties in moving anatomy.

      Therefore, we propose an innovative workaround to overcome these complex issues, namely,
      Mechanically-Assisted and Non-Invasive Ventilation (MANIV). By taking control of the
      patient's breathing, we previously demonstrated that MANIV can safely regularize and even
      reduce tumor motion using a volume-controlled ventilation mode (VC), while a slow ventilation
      mode (SL) can induce repeated DIBH during which the tumor motion is nearly suppressed.
      Although promising, we have to go a step further into the prospective clinical validation of
      MANIV applied to existing motion management techniques.

      A. Preclinical phase:

        1. Clinical implementation of MANIV: development of technical solutions to integrate MANIV
           at each stage of a patient's clinical workflow in our radiotherapy department.

        2. In-house validation and optimization of experimental mathematical models to compute the
           trajectory and amplitude of residual tumor motion during treatment delivery.

      B. Clinical phase:

        1. Optimization of Respiratory Gating by reproducing repeated and stable DIBHs to fix the
           tumor motion for radiotherapy treatment of lung, liver and breast tumors.

        2. Optimization of Tracking procedures by regularizing the breathing and tumor motion with
           VC mode to reduce the treatment duration for real-time lung and liver tumors tracking on
           Accuray Cyberknife® robotic mounted LINAC.

        3. In silico delivred dose assessment of MANIV-optimized Respiratory Gating by Pencil Beam
           Scanning Proton Therapy (PBS-PT).

      At the end of this project, we will provide recommendations for the clinical implementation
      of a wide panel of advanced motion mitigation techniques, which would contribute to a major
      step forward in the management of breathing motion in both photon and proton-therapy.
Radiotherapy of mobile tumors faces many challenges due to breathing-related geometrical
      uncertainties. Breathing amplitude and frequency may deeply and unexpectedly vary from cycle
      to cycle, during a treatment fraction (intra-fraction variation) or between fractions
      (inter-fraction variation) [1]. In Protontherapy (PT), these uncertainties are even worsened
      by the proton range variations within the traversed moving tissues and the interplay effect
      between the tumor and spot scanning beam motions. These effects can unpredictively and
      severely distort dose distribution, and still limit the current indications of PT for
      thoracic/upper-abdomen cancers [2, 3]. Therefore, several motion mitigation strategies have
      been developed:

        -  Margin Strategy: this approach consists in calculating safety margins that encompass
           motion-related uncertainties computed from a prior planning 4D-CT scan. Although simple
           to implement, it inevitably results in futile dose exposure to organs at risk [4].

        -  Gating Strategy: respiratory gating consists in delivering the beam within a time-window
           of the breathing cycle, at the end-expiratory or inspiratory plateau, when the tumor is
           in a predefined stable position. It prevents potentially harmful irradiation of healthy
           tissues by reducing safety margins [4]. During Deep Inspiration Breath Hold (DIBH), the
           patient is asked to hold apneas after deep inspirations to prolong the gating windows
           and the time efficiency of the gating procedure. DIBH has become a standard of care for
           left breast radiotherapy. Indeed, in addition of freezing the tumor motion, it moves
           away the heart from the breast and inflates the lungs, allowing thus to reduce the dose
           to these critical organs at risk [5]. However, for all tumor sites ( breast, lung,
           liver), current beam delivery times typically entail several successive spontaneous BH
           to complete treatment, hence require complex management with onboard imaging to monitor
           the target position [6]. Moreover, repeating spontaneous DIBH requires a good patient's
           compliance and comprehension, which may be a barrier for some patients, and may degrade
           the accuracy of the gating procedure. Various techniques have been investigated to
           improve the tumor position reproducibility over successive BH or to increase BH duration
           to facilitate dose delivery [7,8,9]. However, the patient invariably remains actor of
           his breathing with subsequent unpredictive tumor position variations from BH to BH. As a
           consequence, the accuracy could suffer from residual motion and unpredictable changes
           during spontaneous breath-holds.

        -  Tracking Strategy: this approach relies on motion prediction models derived patient's
           real-time breathing pattern, allowing for the synchronization of the tumor motion with
           the beam motion. Accuray Cyberknife® is a LINAC mounted on a robotic arm designed for
           real-time tumor tracking. A correlation model is built between external motion
           continuously tracked by LEDs placed on the patient and internal tumor position, tracked
           periodically by orthogonal x-rays imagers. The correlation model is updated whenever
           deviations occur due to changes of the breathing pattern [10]. Tracking allows thus to
           significantly reduce the safety margins and to adapt continuously the treatment delivery
           to the breathing pattern [4]. However, the long delivery time of a single fraction, from
           60 to 90 minutes [11], limits its current use in clinical practice. Again, erratic and
           non-reproducible breathing may degrade the accuracy of tracking and will require
           frequent updates of the motion correlation model, at the expense of even longer
           treatment time and discomfort for the patient.

      Until now, none of the current strategy provides an entirely satisfactory solution for motion
      management. The more accurate a technique is, the less efficient it is (treatment time,
      feasibility, ease of clinical implementation), and vice-versa. By taking control of the
      patient breathing, MANIV could solve this complex problem. Parkes et al. showed first that
      MANIV can safely impose a regular breathing pattern on conscious and unsedated patients [12],
      and could mitigate respiratory motion [13, 14]. Our group has further investigated these
      ventilation techniques on healthy volunteers [15] and patients [16] to broaden their
      applicability to radiotherapy of moving tumors. Two ventilation modes appear to be of
      particular interest for radiotherapy :

        -  The Slow Controlled ventilation mode (SL) is a bi-level pressure mode of the mechanical
           ventilator that induces reproducible and repeated DIBH without active patient
           participation. This ventilation mode therefore offers a way to improve the efficiency
           and accuracy of respiratory gating. Indeed, a good physical condition of the patient,
           his compliance or his understanding of the instructions would no longer be necessary
           prerequisites for the feasibility of the treatment. Thus, by relieving the patient of
           his breathing control, MANIV would overcome the limitations of spontaneous DIBH and
           would allow a larger number of patients to benefit from this technique. Moreover, the
           intra- and inter-fraction baseline shift (= mean position variation over time) are
           reduced with MANIV compared to voluntary DIBH [15] and should improve the accuracy of
           the gating procedure. MANIV will thus facilitate both onboard imaging procedure for
           patient positioning and the beam delivery accuracy. In the context of proton therapy,
           freezing the tumor motion thanks to SL mode would allow to treat thoracic and abdominal
           tumors by drastically reducing the motion-related geometrical uncertainties that have
           been prohibitive until now to ensure satisfactory robustness of the planned dose
           distribution.

        -  The Volume Controlled ventilation mode (VC) constraints both breathing rate and tidal
           volume measured from the patient's spontaneous breathing parameters, and imposes a
           completely regular breathing pattern without increasing the tumor baseline shift
           [15,16]. Stabilization of the respiratory pattern over time would be beneficial for
           tracking strategy. We can hypothesize that the regular breathing and tumor motions
           imposed by MANIV would reduce the number of model updates and the overall treatment
           duration, with a substantial gain in efficiency of the technique. To a lesser extent,
           the accuracy of the technique would also be improved [17].

      In summary, our group has already demonstrated that MANIV was feasible and safe on small
      cohorts of volunteers and patients, and significantly improved regularity of
      breathing-related motion or BH monitored by real-time dynamic MRI [15,16]. Based on these
      very encouraging pre-clinical results, MANIV might thus considerably simplify and improve all
      motion management strategies in both photon- and proton therapies. However, further clinical
      investigations are still required in real treatment conditions to validate its use for
      clinical routine. These include the clinical implementation of the ventilator in a LINAC
      environment, and the quantification of the added value of MANIV for the above-mentioned
      mitigation techniques.

      Research project We plan first to implement MANIV in the patient workflow and to validate and
      optimize our onboard imaging procedure to quantify residual motion or motion regularity.
      Then, we will conduct 4 clinical studies, each investigating the added value of MANIV for a
      specific motion management strategy.

      A) Preclinical phase :

      MANIV has been interfaced with the control room of our LINACs to monitor the MANIV breathing
      parameters. Intra-fraction motion will be monitored during gating treatments using Cone-Beam
      CT (CBCT). Computing motion from these devices will require the use of experimental
      mathematical models to infer the three-dimensional trajectory of a tumor from its
      two-dimensional X-rays projections. Five models have been reported in the literature
      [18,19,20,21,22]. The one of Poulsen et al [22] based on a probabilistic approach is the most
      accurate with a submillimetric residual error [23]. We have already validated this method in
      the environnement our treatment machines with a dynamic thorax phantom (model 008A CIRS®),
      and we are now able to analyze intra-fraction motion from imaging data of patients treated on
      our LINACs.

      B) Clinical phase:

      For all clinical studies, subjective and objective patient's tolerance will be monitored
      during MANIV with comfort questionnaires (Likert scales and visual analogue scale) and vital
      parameters (Heartbeat Rate, SpO2, etCO2). Statistical power analysis were performed using the
      PASS 14.0.7 statistical software.

        1. Improving respiratory gating with MANIV-induced DIBH for liver and lung cancers RT:

             -  Design: Non-comparative prospective interventional study.

             -  Population: Patients with primary or secondary hepatic or pulmonary neoplasia
                eligible for radiotherapy.

             -  Method: Irradiation will take place during DIBH induced by the MANIV (Bellavista
                1000, IMTMedical®) with SL mode. Oxygen will be added (FiO2 60%) to safely and
                easily prolong the DIBH duration up to 40-50 seconds to allow the complete delivery
                of a treatment beam [13]. Prior to treatment, a radio-opaque fiducial will be
                implanted in the tumor by an interventional radiologist, to facilitate the tumor
                position monitoring from onboard imaging. Residual tumor baseline shift and motion
                will thus be measured during beam delivery, and used to recompute the optimal
                safety margins that ensure an adequate dose coverage of at least 90% of tumors,
                according to literature recommendations [24]. We will also compare these safety
                margins computed under MANIV condition with those routinely applied in
                free-breathing condition (from a matched retrospective cohort) to estimate the gain
                in terms of margin reduction.

             -  Primary outcome: Feasibility of treatment completion with mechanical-ventilation.

             -  Secondary outcome: a) Proportion of tumors receiving the prescribed dose. b)
                Recalculation of safety margins adapted to the MANIV in SL mode and margin
                reduction compared to conventional free breathing RT.

             -  Statistical power analysis : Considering a poor and good feasibility tresholds of
                70 % and 95 %, respectively and assuming a drop-out of 10 %, a total of 16 patients
                are needed ( alpha level of 0,05 and beta level of 0,8 ).

        2. Improving respiratory gating with MANIV-Induced DIBH for breast RT:

             -  Design: Randomized controlled trial with equiprobable randomization by block of 4
                in 2 arms: the interventional arm will be treated with MANIV-induced DIBH and the
                control arm treated in spontaneous DIBH

             -  Population: Patients with left breast neoplasia eligible for treatment by
                radiotherapy.

             -  Method: Patients in the interventional arm will be treated under the same
                conditions as described above. Optical surface imaging (VisionRT® - Identify®) will
                be used to monitor in real-time the breast position during beam delivery. Based on
                this information, the mean breast displacement will be compared between the two
                arms. The planned dose to the organs at risk (heart, lung) will also be computed
                and compared between both arms. The conversion ratio from the DIBH technique to a
                free breathing treatment will be analyzed in each arm as a surrogate of the DIBH
                strategy efficiency. The treatment will indeed be performed in free breathing when
                the patient will not be able to hold a DIBH for a long enough time for the delivery
                of the treatment.

             -  Primary outcome: mean displacements of the mammary gland during treatment.

             -  Secondary outcomes: a) Planned dose to organs at risk (especially heart and lung)
                b) Proportion of conversion to free-breath in each arm.

             -  Statistical power analysis : 27 patients should be included in each arm to rule an
                additional deviation of 1 mm of the mammary gland during treatment (non-inferiority
                margin of 1 mm) using an independent 2 samples proportion t-test (one-tailed) to
                reach a statistical power of 95 % (alpha error = 2,5 %).

        3. Improving respiratory real-time tracking by VC mode:

             -  Design: Non-comparative prospective interventional study.

             -  Population: Patients with primary or secondary hepatic neoplasia eligible for a
                radiotherapy treatment.

             -  Method: Patients will be ventilated by VC mode during their treatment. For each
                fraction, the treatment time, the number of reconstructions of the tracking model
                and the correlation errors of the model will be collected. The same information
                will be extracted from a matched retrospective cohort treated by tracking in
                spontaneous breathing.

             -  Primary outcome: Mean duration of a fraction.

             -  Secondary outcomes: a) Correlation errors of the model, b) accuracy of the tracking

             -  Statistical power analysis : 20 patients should be included in both cohorts (the
                prospective and retrospective one) to demonstrate a reduction of the mean treatment
                time (effect size = 0.6) with an independent 2 samples t-test (one tailed) to reach
                a statistical power of 80 % (apha error = 5%).

        4. Mechanically-induced breath-holds for gated PBS-PT:

             -  Design: Non-comparative observational prospective study.

             -  Population: Patients included in study n°1

             -  Method: data on tumor position and its residual motion from patients included in
                the study n°1 will be used to compute the planned and in silico delivered dose
                distribution with PBS PT. The MIRO lab (UCL-IREC ) has developed comprehensive
                tools for simulating treatment delivery on patients CT images using the Monte Carlo
                dose engine MCsquare [25], coupled with log-file acquisitions [26]. In this way, we
                will be able to validate our approach in silico in collaboration with IBA, as a
                first step before conducting prospective trials for the clinical validation of this
                approach.

             -  Primary outcome: dose delivered at 95, 98 and 100% of the volume of each tumor.

             -  Statistical power analysis : not applicable. Patients from study n°1 (Improving
                respiratory gating by SL mode) will be included.

                  1. Dhont, J., Vandemeulebroucke, J., Burghelea, M., Poels, K., Depuydt, T., Van
                     Den Begin, R., … Verellen, D. (2018). The long- and short-term variability of
                     breathing induced tumor motion in lung and liver over the course of a
                     radiotherapy treatment. Radiotherapy and Oncology, 126(2), 339 346.
                     https://doi.org/10.1016/j.radonc.2017.09.001

                  2. Bert, C., & Durante, M. (2011). Motion in radiotherapy: particle therapy.
                     Physics in Medicine and Biology, 56(16), R113 R144.
                     https://doi.org/10.1088/0031-9155/56/16/r01

                  3. Korreman, S. S. (2012). Motion in radiotherapy: photon therapy. Physics in
                     Medicine and Biology, 57(23), R161 R191.
                     https://doi.org/10.1088/0031-9155/57/23/r161

                  4. Wolthaus, J. W. H., Sonke, J.-J., van Herk, M., Belderbos, J. S. A., Rossi, M.
                     M. G., Lebesque, J. V., & Damen, E. M. F. (2008). Comparison of Different
                     Strategies to Use Four-Dimensional Computed Tomography in Treatment Planning
                     for Lung Cancer Patients. International Journal of Radiation
                     Oncology*Biology*Physics, 70(4), 1229 1238.
                     https://doi.org/10.1016/j.ijrobp.2007.11.042

                  5. Nissen, H. D., & Appelt, A. L. (2013). Improved heart, lung and target dose
                     with deep inspiration breath hold in a large clinical series of breast cancer
                     patients. Radiotherapy and Oncology, 106(1), 28 32.
                     https://doi.org/10.1016/j.radonc.2012.10.016

                  6. Shiinoki, T., Hanazawa, H., Yuasa, Y., Fujimoto, K., Uehara, T., & Shibuya, K.
                     (2017). Verification of respiratory-gated radiotherapy with new real-time
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allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Multicentric prospective interventional or retrospective observational study depending on the sub-part considered. It is segmented into 5 sub-parts each investigating the interest of MANIV for a specific motion management technique.
primary purpose: Treatment
masking: None (Open Label)
measure: Validation of MANIV-optimized Gating strategy for breast tumors
time frame: through study completion, an average of 3 weeks
description: mean breast gland 3D displacements during treatment delivery.
measure: Validation of MANIV-optimized Gating strategy for lung and liver tumors
time frame: through study completion, an average of 2 weeks
description: Proportion of patients successfully treated with MANIV
measure: Validation of MANIV-optimized Tracking strategy
time frame: through study completion, an average of 2 weeks
description: Average time required to deliver a fraction
measure: In silico evaluation of viability with treatment by protontherapy in SL mode
time frame: through study completion, an average of 2 weeks
description: % of CTV volume receiving at least a given dose level by patient
arm group label: Arm N°1 - Standard treatment-Breast DIBH
arm group type: Active Comparator
description: Patients will be treated during spontaneous breath hold wich is considered as the gold-standard radiotherapy treatment for left breast cancer.
arm group label: Arm N°2 - Interventional -Breast MANIV DIBH
arm group type: Experimental
description: Irradiation will take place during DIBH induced by MANIV (Bellavista 1000, IMTMedical®) with SL mode. Oxygen will be added (FiO2 60%) to safely and easily prolong the DIBH duration up to 30 seconds to allow the complete delivery of a treatment beam.
arm group label: Arm N°3 - Interventional -Liver/Lung MANIV DIBH
arm group type: Experimental
description: Irradiation will take place during DIBH induced by the MANIV (Bellavista 1000, IMTMedical®) with SL mode. Oxygen will be added (FiO2 60%) to safely and easily prolong the DIBH duration up to 30 seconds to allow the complete delivery of a treatment beam [13]. Prior to treatment, a radio-opaque fiducial will be implanted in the tumor by an interventional radiologist, to facilitate the tumor position monitoring from onboard imaging. Residual tumor baseline shift and motion will thus be measured during beam delivery, and used to recompute the optimal safety margins that ensure an adequate dose coverage of at least 90% of tumors, according to literature recommendations [24]. We will also compare these safety margins computed under MANIV condition with those routinely applied in free-breathing condition to estimate the gain in terms of margin reduction.
arm group label: Arm N°4 - Interventional -Liver/Lung MANIV VC
arm group type: Experimental
description: Patients will be ventilated by VC mode during their treatment. For each fraction, the treatment time, the number of reconstructions of the tracking model and the correlation errors of the model will be collected. The same information will be extracted from a matched retrospective cohort treated by tracking in spontaneous breathing.
arm group label: Arm N°5 -Liver/Lung MANIV DIBH for PT
arm group type: Other
description: Data on tumor position and its residual motion from patients included in the arm n°3 will be used to compute the planned and in silico delivered dose distribution with PBS PT. The MIRO lab (UCLouvain - IREC) has developed comprehensive tools for simulating treatment delivery on patients CT images using the Monte Carlo dose engine MCsquare [25], coupled with log-file acquisitions [26]. In this way, we will be able to validate our approach in silico in collaboration with IBA, as a first step before conducting prospective trials for the clinical validation of this approach.
intervention type: Device
intervention name: MANIV
description: mechanical ventilator (Bellavista 1000, IMTmedical) will be used on Varian® Halcyon LINAC and Infinity Elekta® linac
arm group label: Arm N°2 - Interventional -Breast MANIV DIBH
arm group label: Arm N°3 - Interventional -Liver/Lung MANIV DIBH
arm group label: Arm N°4 - Interventional -Liver/Lung MANIV VC
arm group label: Arm N°5 -Liver/Lung MANIV DIBH for PT
intervention type: Other
intervention name: Spontaneous DIBH
description: performed on Varian® Halcyon LINAC and Infinity Elekta® linac
arm group label: Arm N°1 - Standard treatment-Breast DIBH
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Geneviève Van Ooteghem, MD,PhD
role: Study Chair
affiliation: Cliniques Universitaires Saint-Luc, Brussels, Belgium
last name: David Pasquier, MD,PhD
role: Study Chair
affiliation: Centre Oscar Lambret, Lille, France
last name: Xavier Geets, MD,PhD
role: Principal Investigator
affiliation: Cliniques Universitaires Saint-Luc, Brussels, Belgium
last name: Loïc Vander Veken, MD
role: Study Chair
affiliation: Cliniques Universitaires Saint-Luc,Brussels, Belgium
facility: 
country: Belgium
responsible party type: Sponsor