. Radio-opaque markers are recommended for image-guided radiotherapy in liver stereotactic ablative radiotherapy (SABR), but their implantation is invasive. We evaluate in this
study the feasibility ...of cone-beam computed tomography-guided stereotactic online-adaptive radiotherapy (CBCT-STAR) to propagate the target volumes without implanting radio-opaque markers and assess its consequence on the margin that should be used in that context.
. An emulator of a CBCT-STAR-dedicated treatment planning system was used to generate plans for 32 liver SABR patients. Three target volume propagation strategies were compared, analysing the volume difference between the GTV
and the GTV
, the vector lengths between their centres of mass (
), and the 95th percentile of the Hausdorff distance between these two volumes (HD95). These propagation strategies were: (1) structure-guided deformable registration with deformable GTV propagation; (2) rigid registration with rigid GTV propagation; and (3) image-guided deformable registration with rigid GTV propagation. Adaptive margin calculation integrated propagation errors, while interfraction position errors were removed. Scheduled plans (Plan
) and daily-adapted plans (Plan
) were compared for each treatment fraction.
The image-guided deformable registration with rigid GTV propagation was the best propagation strategy regarding to
(mean: 4.3 +/- 2.1 mm), HD95 (mean 4.8 +/- 3.2 mm) and volume preservation between GTV
and GTV
. This resulted in a planning target volume (PTV) margin increase (+69.1% in volume on average). Online adaptation (Plan
) reduced the violation rate of the most important dose constraints ('priority 1 constraints', 4.2 versus 0.9%, respectively;
< 0.001) and even improved target volume coverage compared to non-adaptive plans (Plan
).
. Markerless CBCT-STAR for liver tumours is feasible using Image-guided deformable registration with rigid GTV propagation. Despite the cost in terms of PTV volumes, daily adaptation reduces constraints violation and restores target volumes coverage.
•MANIV is a safe breathing-constraining technique that is well-tolerated by patients.•The volume-controlled mode reduces inter-session variation in tumour motion amplitude and stabilizes the ...respiratory rate, which may facilitate tracking strategies.•The shallow-controlled mode reduces the tumour motion amplitude while ensuring regular, rapid, and shallow breathing that may benefit margin strategies.•The slow-controlled mode repeats short end-inspiratory plateaus (>15 s), well tolerated by patients and potentially useful for gated delivery.
Current motion mitigation strategies, like margins, gating, and tracking, deal with geometrical uncertainties in the tumour position, induced by breathing during radiotherapy (RT). However, they often overlook motion variability in amplitude, respiratory rate, or baseline position, when breathing spontaneously. Consequently, this may negatively affect the delivered dose conformality in comparison to the plan. We previously demonstrated on volunteers that 3 different modes of mechanically-assisted and non-invasive ventilation (MANIV) may reduce variability in breathing motion. The volume-controlled mode (VC) constraints the amplitude and respiratory rate (RR) in physiologic condition. The shallow-controlled mode (SH), derived from VC, increases the RR and decreases amplitude. The slow-controlled mode (SL) induces repeated breath holds with constrained ventilation pressure. In this study, we compared these mechanical ventilation modes to spontaneous breathing or breath hold and assessed their tolerance and effects on internal tumour motion in patients receiving RT.
The VC and SH modes were evaluated in ten patients with lung or liver cancers (cohort A). The SL mode was evaluated in 12 left breast cancer patients (cohort B). After a training and simulation session, the patients underwent 2 MRI sessions to analyze the internal motion of breast and tumour.
MANIV was well tolerated, without any adverse events or oxymetric changes, even in patients with respiratory comorbidities. In cohort A, when compared to spontaneous breathing (SP), VC reduced significantly inter-session variations of the tumour motion amplitude (p = 0.01), as well as intra- and inter-session variations of the RR (p < 0.05). As to SH, the RR increased, while its variations within and across sessions decreased when compared to SP (p < 0.001). SH reduced the median amplitude of the tumour motion by 6.1 mm or 38.2% (p ≤ 0.01) compared to VC. In cohort B, breast position stability over the end-inspiratory plateaus obtained spontaneously or with SL remained similar. Median duration of the plateaus in SL was 16.6 s.
MANIV is a safe and well tolerated ventilation technique for patients receiving radiotherapy. MANIV could thus make current motion mitigation strategies less critical and more robust. Clinical implementation might be considered, provided the ventilation mode is carefully selected with respect to the treatment indication and patient individualities.
With the development of immune checkpoint inhibitors (ICIs), the tumour immune microenvironment (TIME) has been increasingly considered to improve cancer management. The TIME of metastatic lesions is ...strongly influenced by the underlying immune contexture of the organ in which they are located. The metastatic location itself appears to be an important prognostic factor in predicting outcomes after ICI treatment in cancer patients. Patients with liver metastases are less likely to respond to ICIs than patients with metastases in other organs, likely due to variations in the metastatic TIME. Combining additional treatment modalities is an option to overcome this resistance. Radiotherapy (RT) and ICIs have been investigated together as an option to treat various metastatic cancers. RT can induce a local and systemic immune reaction, which can promote the patient's response to ICIs. Here, we review the differential impact of the TIME according to metastatic location. We also explore how RT-induced TIME modifications could be modulated to improve outcomes of RT-ICI combinations.
•MANIV can safely stabilize and modulate the breathing pattern.•Volume-controlled mode stabilizes the breathing pattern in respect with physiology.•Shallow-controlled mode lowers the motion amplitude ...by increasing the breathing rate.•Slow-controlled mode gives more reproducible breath holds than voluntary breath holds.•MANIV improves intra- and inter-session reproducibility.•Photon- and proton-therapy can benefit of this active breathing management technique.
When using highly conformal radiotherapy techniques, a stabilized breathing pattern could greatly benefit the treatment of mobile tumours. Therefore, we assessed the feasibility of Mechanically-assisted non-invasive ventilation (MANIV) on unsedated volunteers, and its ability to stabilize and modulate the breathing pattern over time.
Twelve healthy volunteers underwent 2 sessions of dynamic MRI under 4 ventilation modes: spontaneous breathing (SP), volume-controlled mode (VC) that imposes regular breathing in physiologic conditions, shallow-controlled mode (SH) that intends to lower amplitudes while increasing the breathing rate, and slow-controlled mode (SL) that mimics end-inspiratory breath-holds. The last 3 modes were achieved under respirator without sedation. The motion of the diaphragm was tracked along the breathing cycles on MRI images and expressed in position, breathing amplitude, and breathing period for intra- and inter-session analyses. In addition, end-inspiratory breath-hold duration and position stability were analysed during the SL mode.
MANIV was well-tolerated by all volunteers, without adverse event. The MRI environment led to more discomfort than MANIV itself. Compared to SP, VC and SH modes improved the inter-session reproducibility of the amplitude (by 43% and 47% respectively) and significantly stabilized the intra- and inter-session breathing rate (p < 0.001). Compared to VC, SH mode significantly reduced the intra-session mean amplitude (36%) (p < 0.002), its variability (42%) (p < 0.001), and the intra-session baseline shift (26%) (p < 0.001). The SL mode achieved end-inspiratory plateaus lasting more than 10 s.
MANIV offers exciting perspectives for motion management. It improves its intra- and inter-session reproducibility and should facilitate respiratory tracking, gating or margin techniques for both photon and proton treatments.
Defining dosimetric rules to automatically detect patients requiring adaptive radiotherapy (ART) is not straightforward, and most centres perform ad-hoc ART with no specific protocol. This study aims ...to propose and analyse different steps to design a protocol for dosimetrically triggered ART of head and neck (H&N) cancer. As a proof-of-concept, the designed protocol was applied to patients treated in TomoTherapy units, using their available software for daily MVCT image and dose accumulation.
An initial protocol was designed by a multidisciplinary team, with a set of flagging criteria based only on dose-volume metrics, including two action levels: (1) surveillance (orange flag), and (2) immediate verification (red flag). This protocol was adapted to the clinical needs following an iterative process. First, the protocol was applied to 38 H&N patients with daily imaging. Automatic software generated the daily contours, recomputed the daily dose and flagged the dosimetric differences with respect to the planning dose. Second, these results were compared, by a sensitivity/specificity test, to the answers of a physician. Third, the physician, supported by the multidisciplinary team, performed a self-analysis of the provided answers and translated them into mathematical rules in order to upgrade the protocol. The upgraded protocol was applied to different definitions of the target volume (i.e. deformed CTV + 0, 2 and 4 mm), in order to quantify how the number of flags decreases when reducing the CTV-to-PTV margin.
The sensitivity of the initial protocol was very low, specifically for the orange flags. The best values were 0.84 for red and 0.15 for orange flags. After the review and upgrade process, the sensitivity of the upgraded protocol increased to 0.96 for red and 0.84 for orange flags. The number of patients flagged per week with the final (upgraded) protocol decreased in median by 26% and 18% for red and orange flags, respectively, when reducing the CTV-to-PTV margin from 4 to 2 mm. This resulted in only one patient flagged at the last fraction for both red and orange flags.
Our results demonstrate the value of iterative protocol design with retrospective data, and shows the feasibility of automatically-triggered ART using simple dosimetric rules to mimic the physician's decisions. Using a proper target volume definition is important and influences the flagging rate, particularly when decreasing the CTV-to-PTV margin.
•CBCT-guided online-ART is feasible and an option for localised colon cancer.•Online-ART compensates for tumour and abdominal organs interfraction motion.•Intrafraction variations need to be managed ...using different strategies.•Daily CTV delineation on CBCT requires radio-opaque marker implantation.•Online-ART for localised colon cancer can be performed in an acceptable time frame.
We report the case of a medically inoperable patient with localised colon cancer. Due to symptomatic bleeding, definitive radiotherapy (5 daily fractions of 5 Gy) has been performed using cone-beam computed tomography-based online-adaptive radiotherapy (ART). Online-ART enables compensation of interfraction motion of abdominal organs by performing daily delineation of organs at risk (OARs) and target volumes. Daily treatment replanning maximised target volume coverage while lowering the dose to OARs. Intrafraction variation of the tumour was still significant and had to be incorporated in the planning target volume margin computation. After the treatment, the patient did not develop any acute radiotherapy-induced adverse events and had no further rectal bleeding either at the end of the radiotherapy or at oncological follow-up 4 months later. Online-ART for colon cancer is feasible and is a valuable alternative when surgery is not an option.
•Reproducibility/Stability of MANIV-DIBH is non-inferior to surface-guided DIBH.•A better cardiopulmonary protection is achieved with mechanical ventilation.•Comfort and treatment time with MANIV are ...similar to surface-guided DIBH.•MANIV enables better inter-fraction heart repositioning.
Deep inspiration breath-hold (DIBH) protects critical organs-at-risk (OARs) for adjuvant breast radiotherapy. Guidance systems e.g. surface guided radiation therapy (SGRT) improve the positional breast reproducibility and stability during DIBH. In parallel, OARs sparing with DIBH is enhanced through different techniques e.g. prone position, continuous positive airway pressure (CPAP). By inducing repeated DIBH with the same level of positive pressure, mechanically-assisted and non-invasive ventilation (MANIV) could potentially combine these DIBH optimizations.
We conducted a randomized, open-label, multicenter and single-institution non-inferiority trial. Sixty-six patients eligible for adjuvant left whole-breast radiotherapy in supine position were equally assigned between mechanically-induced DIBH (MANIV-DIBH) and voluntary DIBH guided by SGRT (sDIBH). The co-primary endpoints were positional breast stability and reproducibility with a non-inferiority margin of 1 mm. Secondary endpoints were tolerance assessed daily via validated scales, treatment time, dose to OARs and their inter-fraction positional reproducibility.
Differences between both arms for positional breast reproducibility and stability occurred at a sub-millimetric level (p < 0.001 for non-inferiority). The left anterior descending artery near-max dose (14,6 ± 12,0 Gy vs. 7,7 ± 7,1 Gy, p = 0,018) and mean dose (5,0 ± 3,5 Gy vs. 3,0 ± 2,0 Gy, p = 0,009) were improved with MANIV-DIBH. The same applied for the V5Gy of the left ventricle (2,4 ± 4,1 % vs. 0,8 ± 1,6 %, p = 0,001) as well as for the left lung V20Gy (11,4 ± 2,8 % vs. 9,7 ± 2,7 %, p = 0,019) and V30Gy (8,0 ± 2,6 % vs. 6,5 ± 2,3 %, p = 0,0018). Better heart’s inter-fraction positional reproducibility was observed with MANIV-DIBH. Tolerance and treatment time were similar.
Mechanical ventilation provides the same target irradiation accuracy as with SGRT while better protecting and repositioning OARs.
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•Directional MidP method incorporates motion directionality in PTV definition.•Higher 4D D95% and D99% are achieved with the proposed method.•PTV volume is similar compared to ...classical MidP strategy.
Planning target volume (PTV) definition based on Mid-Position (Mid-P) strategy typically integrates breathing motion from tumor positions variances along the conventional axes of the DICOM coordinate system. Tumor motion directionality is thus neglected even though it is one of its stable characteristics in time. We therefore propose the directional MidP approach (MidP dir), which allows motion directionality to be incorporated into PTV margins. A second objective consists in assessing the ability of the proposed method to better take care of respiratory motion uncertainty.
11 lung tumors from 10 patients with supra-centimetric motion were included. PTV were generated according to the MidP and MidP dir strategies starting from planning 4D CT.
PTVMidP dir volume didn’t differ from the PTVMidP volume: 31351 mm3 IC95% 17242–45459 vs. 31003 mm3 IC95% 17347–44659, p = 0.477 respectively. PTVMidP dir morphology was different and appeared more oblong along the main motion axis. The relative difference between 3D and 4D doses was on average 1.09%, p = 0.011 and 0.74%, p = 0.032 improved with directional MidP for D99% and D95%. D2% was not significantly different between both approaches. The improvement in dosimetric coverage fluctuated substantially from one lesion to another and was all the more important as motion showed a large amplitude, some obliquity with respect to conventional axes and small hysteresis.
Directional MidP method allows tumor motion to be taken into account more tightly as a geometrical uncertainty without increasing the irradiation volume.
We developed a training protocol based on Intrapulmonary Percussive Ventilation in order to prolong breath-hold while nearly suppressing the thorax motion. This protocol allowed ten subjects to ...achieve a 20-minutes-breath-hold, while reducing the residual surface motion to 1 mm around its mean position for more than 95% of the breath-hold duration.
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