Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04457102 |
| Other study ID # |
2020/03FEV/065 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
July 3, 2020 |
| Est. completion date |
September 30, 2024 |
Study information
| Verified date |
May 2023 |
| Source |
Cliniques universitaires Saint-Luc- Université Catholique de Louvain |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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.
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