Characterization of the IDENTIFYTM surface scanning system for radiation therapy setup on a closed-bore linac.

PURPOSE: In radiation therapy, surface guidance can be used for patient setup and intra-fraction motion monitoring. The surface guided radiation therapy (SGRT) system from Varian Medical systems, IDENTIFYTM, consists of three pods, including cameras and a random pattern projector, mounted on the ceiling. The information captured by the cameras is used to make a reconstruction of the surface. The aim of the study was to assess the technical performance of this SGRT system on a closed-bore linac. METHODS: Phantom measurements were performed to assess the accuracy, precision, reproducibility and temporal stability of the system, both in align and in load position. Translations of the phantoms in lateral, longitudinal, and vertical direction, and rotations around three axes (pitch, roll and yaw) were performed with an accurate, in-house built, positioning stage. Different phantom geometries and different surface colors were used, and various ambient light intensities were tested. RESULTS: The accuracy of the IDENTIFYTM system at the closed-bore linac was 0.07 mm and 0.07 degrees at load position, and 0.06 mm and 0.01 degrees at align position for the white head phantom. The precision was 0.02 mm and 0.02 degrees in load position, and 0.01 mm and 0.02 degrees in align position. The accuracy for the Penta-Guide phantom was comparable to the white head phantom, with 0.06 mm and 0.01 degrees in align position. The system was slightly less accurate for translations of the CIRS lung phantom in align position (0.20 mm, 0.05 degrees). Reproducibility measurements showed a variation of 0.02 mm in load position. Regarding the temporal stability, the maximum drift over 30 min was 0.33 mm and 0.02 degrees in load position. No effect of ambient light level on the accuracy of the IDENTIFYTM system was observed. Regarding different surface colors, the accuracy of the system for a black phantom was slightly worse compared to a white surface, but not clinical relevant. CONCLUSION: The IDENTIFYTM system can adequately be used for motion monitoring on a closed-bore linac with submillimeter accuracy. The results of the performed measurements meet the clinical requirements described in the guidelines of the AAPM and the ESTRO.

Geometrical analysis for motion monitoring of rigid bodies with optical surface scanning in radiation oncology.

BACKGROUND AND PURPOSE: Surface guided radiotherapy can be used to improve patient setup and for accurate intra-fraction motion monitoring in correspondence to the isocenter. For a clinical relevant motion analysis the actual displacement of the entire clinical target volume (CTV) is necessary. Therefore, the aim of this study was to develop a novel assessment method for intra-fraction motion for rigid body structures based on motion data and a geometrical analysis. MATERIALS AND METHODS: A threshold value on the volume coverage (VC(t)) of the CTV by the planning target volume (PTV) was proposed as online motion monitoring method. Moreover, offline analysis was performed by using heat maps and by calculating VCx, the volume coverage for at least x% of treatment time. The method was applied retrospectively to patient treatment data for whole brain radiation treatment without a thermoplastic mask. RESULTS: In 132 out of 142 fractions in total the proportion of the CTV that was inside the PTV for at least 99% of the time (VC99) was more than 95%, for a CTV-to-PTV margin of 5 mm. The source-voxel heat map showed which part of the CTV had a reduced coverage and the target heat map showed the movement of the CTV. CONCLUSION: Instead of using an action threshold on the movements of the isocenter, a threshold on the VC(t) of the CTV by the PTV was proposed. The heat maps and resulting values of VCx can be used to adapt the VC(t) threshold or the CTV-to-PTV margin for subsequent fractions.

Radiotherapy quality assurance for mesorectum treatment planning within the multi-center phase II STAR-TReC trial: Dutch results.

BACKGROUND: The STAR-TReC trial is an international multi-center, randomized, phase II study assessing the feasibility of short-course radiotherapy or long-course chemoradiotherapy as an alternative to total mesorectal excision surgery. A new target volume is used for both (chemo)radiotherapy arms which includes only the mesorectum. The treatment planning QA revealed substantial variation in dose to organs at risk (OAR) between centers. Therefore, the aim of this study was to determine the treatment plan variability in terms of dose to OAR and assess the effect of a national study group meeting on the quality and variability of treatment plans for mesorectum-only planning for rectal cancer. METHODS: Eight centers produced 25 × 2 Gy treatment plans for five cases. The OAR were the bowel cavity, bladder and femoral heads. A study group meeting for the participating centers was organized to discuss the planning results. At the meeting, the values of the treatment plan DVH parameters were distributed among centers so that results could be compared. Subsequently, the centers were invited to perform replanning if they considered this to be necessary. RESULTS: All treatment plans, both initial planning and replanning, fulfilled the target constraints. Dose to OAR varied considerably for the initial planning, especially for dose levels below 20 Gy, indicating that there was room for trade-offs between the defined OAR. Five centers performed replanning for all cases. One center did not perform replanning at all and two centers performed replanning on two and three cases, respectively. On average, replanning reduced the bowel cavity V20Gy by 12.6%, bowel cavity V10Gy by 22.0%, bladder V35Gy by 14.7% and bladder V10Gy by 10.8%. In 26/30 replanned cases the V10Gy of both the bowel cavity and bladder was lower, indicating an overall lower dose to these OAR instead of a different trade-off. In addition, the bowel cavity V10Gy and V20Gy showed more similarity between centers. CONCLUSIONS: Dose to OAR varied considerably between centers, especially for dose levels below 20 Gy. The study group meeting and the distribution of the initial planning results among centers resulted in lower dose to the defined OAR and reduced variability between centers after replanning. TRIAL REGISTRATION: The STAR-TReC trial, ClinicalTrials.gov Identifier: NCT02945566. Registered 26 October 2016, https://clinicaltrials.gov/ct2/show/NCT02945566).

Thermal combination therapies for local drug delivery by magnetic resonance-guided high-intensity focused ultrasound.

Several thermal-therapy strategies such as thermal ablation, hyperthermia-triggered drug delivery from temperature-sensitive liposomes (TSLs), and combinations of the above were investigated in a rhabdomyosarcoma rat tumor model (n = 113). Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) was used as a noninvasive heating device with precise temperature control for image-guided drug delivery. For the latter, TSLs were prepared, coencapsulating doxorubicin (dox) and [Gd(HPDO3A)(H2O)], and injected in tumor-bearing rats before MR-HIFU treatment. Four treatment groups were defined: hyperthermia, ablation, hyperthermia followed by ablation, or no HIFU. The intratumoral TSL and dox distribution were analyzed by single-photon emission computed tomography (SPECT)/computed tomography (CT), autoradiography, and fluorescence microscopy. Dox biodistribution was quantified and compared with that of nonliposomal dox. Finally, the treatment efficacy of all heating strategies plus additional control groups (saline, free dox, and Caelyx) was assessed by tumor growth measurements. All HIFU heating strategies combined with TSLs resulted in cellular uptake of dox deep into the interstitial space and a significant increase of tumor drug concentrations compared with a treatment with free dox. Ablation after TSL injection showed [Gd(HPDO3A)(H2O)] and dox release along the tumor rim, mirroring the TSL distribution pattern. Hyperthermia either as standalone treatment or before ablation ensured homogeneous TSL, [Gd(HPDO3A)(H2O)], and dox delivery across the tumor. The combination of hyperthermia-triggered drug delivery followed by ablation showed the best therapeutic outcome compared with all other treatment groups due to direct induction of thermal necrosis in the tumor core and efficient drug delivery to the tumor rim.

Accuracy of dose calculations on kV cone beam CT images of lung cancer patients.

PURPOSE: To develop a clinically feasible method for dose calculations on cone beam CT (CBCT) images of two different vendors, and to determine the accuracy of these dose calculations for lung cancer patients. METHODS: Lung cancer patients with CBCT imaging (n = 10 for Elekta, n = 6 for Varian) and a repeated planning CT scan on the same day were selected. For CBCT dose calculations, an adapted Hounsfield units-to-mass density table (HU table) was used which was obtained by comparing CT values of corresponding points on the CBCT and the repeated planning CT scan. Dose calculations with three different HU tables were compared: a patient-specific, a general thorax-CBCT, and the standard CT HU table. Planning CT data were used to compensate for the limited field of view (FOV) (Elekta) or scan length (Varian) of the CBCT. For evaluation, clinically relevant dose metrics were compared between the repeated CT and CBCT to assess the accuracy of dose calculations on CBCT for both vendors. RESULTS: For both vendors, isodose lines and dose volume histograms were very similar between dose calculation on CBCT and CT. For Varian, average differences between CT and CBCT dose calculations were 2%-3% for most dose metrics when the standard CT HU table was used. A better agreement was observed when a thorax-CBCT HU table was used, with differences of 1%-2%. No added value was found by using a patient-specific HU table, showing similar results as the general thorax-CBCT HU table. For Elekta, the dose metrics showed large deviations when the CT HU table was used, but using a patient-specific HU table resulted in similar accuracy as for Varian CBCT dose calculations, with average differences between repeated CT and CBCT dose metrics below 3%, and for most dose metrics even below 2%. CONCLUSIONS: Differences between Elekta and Varian CBCT, including hardware, reconstruction software, HU calibration, FOV, and scan length, resulted in different challenges for CBCT dose calculations for the different vendors. For Elekta CBCT scans, the procedure with a patient-specific HU table resulted in similar accuracy as for Varian CBCT dose calculations with a general HU correction for all thorax patients. The vendor-specific corrective methods used in this study resulted in dose calculations feasible for treatment re-evaluation for both Elekta and Varian CBCT scans.

Temperature-sensitive paramagnetic liposomes for image-guided drug delivery: Mn(2+) versus [Gd(HPDO3A)(H2O)].

Temperature-sensitive liposomes (TSLs) loaded with doxorubicin (Dox), and Magnetic Resonance Imaging contrast agents (CAs), either manganese (Mn(2+)) or [Gd(HPDO3A)(H2O)], provide the advantage of drug delivery under MR image guidance. Encapsulated MRI CAs have low longitudinal relaxivity (r1) due to limited transmembrane water exchange. Upon triggered release at hyperthermic temperature, the r1 will increase and hence, provides a means to monitor drug distribution in situ. Here, the effects of encapsulated CAs on the phospholipid bilayer and the resulting change in r1 were investigated using MR titration studies and (1)H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles. Our results show that Mn(2+) interacted with the phospholipid bilayer of TSLs and consequently, reduced doxorubicin retention capability at 37°C within the interior of the liposomes over time. Despite that, Mn(2+)-phospholipid interaction resulted in higher r1 increase, from 5.1±1.3mM(-1)s(-1) before heating to 32.2±3mM(-1)s(-1) after heating at 60MHz and 37°C as compared to TSL(Gd,Dox) where the longitudinal relaxivities before and after heating were 1.2±0.3mM(-1)s(-1) and 4.4±0.3mM(-1)s(-1), respectively. Upon heating, Dox was released from TSL(Mn,Dox) and complexation of Mn(2+) to Dox resulted in a similar Mn(2+) release profile. From 25 to 38°C, r1 of [Gd(HPDO3A)(H2O)] gradually increased due to increase transmembrane water exchange, while no Dox release was observed. From 38°C, the release of [Gd(HPDO3A)(H2O)] and Dox was irreversible and the release profiles coincided. By understanding the non-covalent interactions between the MRI CAs and phospholipid bilayer, the properties of the paramagnetic TSLs can be tailored for MR guided drug delivery.

SPECT/CT imaging of temperature-sensitive liposomes for MR-image guided drug delivery with high intensity focused ultrasound.

The goal of this study was to investigate the blood kinetics and biodistribution of temperature-sensitive liposomes (TSLs) for MR image-guided drug delivery. The co-encapsulated doxorubicin and [Gd(HPDO3A)(H2O)] as well as the ¹¹¹In-labeled liposomal carrier were quantified in blood and organs of tumor bearing rats. After TSL injection, mild hyperthermia (T=42 °C) was induced in the tumor using high intensity focused ultrasound under MR image-guidance (MR-HIFU). The biodistribution of the radiolabeled TSLs was investigated using SPECT/CT imaging, where the highest uptake of ¹¹¹In-labeled TSLs was observed in the spleen and liver. The MR-HIFU-treated tumors showed 4.4 times higher liposome uptake after 48 h in comparison with controls, while the doxorubicin concentration was increased by a factor of 7.9. These effects of HIFU-treatment are promising for applications in liposomal drug delivery to tumors.

Magnetic resonance guided high-intensity focused ultrasound mediated hyperthermia improves the intratumoral distribution of temperature-sensitive liposomal doxorubicin.

OBJECTIVES: The aim of this study was to investigate the intratumoral distribution of a temperature-sensitive liposomal carrier and its encapsulated compounds, doxorubicin, and a magnetic resonance (MR) imaging contrast agent after high-intensity focused ultrasound (HIFU)-mediated hyperthermia-induced local drug release. MATERIALS AND METHODS: (111)In-labeled temperature-sensitive liposomes encapsulating doxorubicin and [Gd(HPDO3A) (H(2)O)] were injected intravenously in the tail vein of rats (n = 12) bearing a subcutaneous rhabdomyosarcoma tumor on the hind leg. Immediately after the injection, local tumor hyperthermia (2 × 15 minutes) was applied using a clinical 3 T MR-HIFU system. Release of [Gd(HPDO3A)(H(2)O)] was studied in vivo by measuring the longitudinal relaxation rate R(1) with MR imaging. The presence of the liposomal carriers and the intratumoral distribution of doxorubicin were imaged ex vivo with autoradiography and fluorescence microscopy, respectively, for 2 different time points after injection (90 minutes and 48 hours). RESULTS: In hyperthermia-treated tumors, radiolabeled liposomes were distributed more homogeneously across the tumor than in the control tumors (coefficient of variation(hyp, 90 min) = 0.7 ± 0.2; coefficient of variation(cntrl, 90 min) = 1.1 ± 0.2). At 48 hours after injection, the liposomal accumulation in the tumor was enhanced in the hyperthermia group in comparison with the controls. A change in R(1) was observed in the HIFU-treated tumors, suggesting release of the contrast agent. Fluorescence images showed perivascular doxorubicin in control tumors, whereas in the HIFU-treated tumors, the delivered drug was spread over a much larger area and also taken up by tumor cells at a larger distance from blood vessels. CONCLUSIONS: Treatment with HIFU hyperthermia not only improved the immediate drug delivery, bioavailability, and intratumoral distribution but also enhanced liposomal accumulation over time. The sum of these effects may have a significant contribution to the therapeutic outcome.

In vivo temperature controlled ultrasound-mediated intracellular delivery of cell-impermeable compounds.

Many chemotherapeutic drugs are characterized by high systemic toxicity and/or suffer from limited bioavailability. Thermosensitive liposomes (TSLs) encapsulating drugs in their aqueous lumen are promising activatable nanocarriers for ultrasound (US)-mediated drug delivery in response to mild hyperthermia. On the other hand, US is known to locally break biological barriers and as a consequence enable internalization of molecules. In this work, a two-step protocol for intracellular delivery of cell-impermeable molecules comprising of US-induced permeabilization followed by temperature-controlled release of the model drug from thermosensitive liposomes has been developed. TSLs containing TO-PRO-3, a cell-impermeable molecule that displays a significant increase in fluorescence upon binding to nucleic acids thus serving as a 'sensor' for internalization have been prepared and characterized in detail. US-mediated permeabilization followed by temperature-controlled release was applied to tumor bearing mice following i.v. injection of TSLs and microbubbles. The efficacy of this approach was evaluated by in vivo fluorescence imaging followed by histological analysis. A 2.4-fold increase of fluorescence signal was observed and intracellular delivery of TO-PRO-3 was confirmed by a characteristic nuclear staining. These results demonstrate the feasibility of novel drug delivery system to tumors comprising of local cell permeabilization by US followed by in situ release of the payload from thermosensitive liposomes. Possible applications include local and controlled intracellular delivery of molecules with otherwise limited bioavailability.

Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive liposomes: an in vivo proof-of-concept study.

Temperature-sensitive liposomes (TSLs) co-encapsulating doxorubicin and 250 mM [Gd(HPDO3A)(H2O)] were evaluated for HIFU-mediated drug delivery under MR image guidance. In vitro studies showed simultaneous and quantitative release of the drug and the MRI contrast agent from the lumen of the TSLs at 42°C, while no leakage was observed over 1 h at 37°C. In a proof-of-concept study, local hyperthermia has been applied for 30 min in 9L rat tumors using a clinical MR-HIFU system. The local temperature-triggered release of [Gd(HPDO3A)(H2O)] was monitored with interleaved T1 mapping of the tumor tissue. A good correlation between the ΔR1, the uptake of doxorubicin and the gadolinium concentration in the tumor was found, implying that the in vivo release of doxorubicin from TSLs can be probed in situ with the longitudinal relaxation time of the co-released MRI contrast agent.

Temperature-sensitive liposomes for doxorubicin delivery under MRI guidance.

Local drug delivery of doxorubicin holds promise to improve the therapeutic efficacy and to reduce toxicity profiles. Here, we investigated the release of doxorubicin and [Gd(HPDO3A)(H(2)O)] from different temperature-sensitive liposomes for applications in temperature-induced drug delivery under magnetic resonance image guidance. In particular, two temperature-sensitive systems composed of DPPC:MPPC:DPPE-PEG2000 (low temperature-sensitive liposomes, LTSL) and DPPC:HSPC:cholesterol:DPPE-PEG2000 (traditional temperature-sensitive liposomes, TTSL) were investigated. The co-encapsulation of [Gd(HPDO3A)(H(2)O)], a clinically approved MRI contrast agent, did not influence the encapsulation and release of doxorubicin. The LTSL system showed a higher leakage of doxorubicin at 37 degrees C, but a faster release of doxorubicin at 42 degrees C compared to the TTSL system. Furthermore, the rapid release of both doxorubicin and the MRI contrast agent from the liposomes occurred near the melting phase transition temperature, making it possible to image the release of doxorubicin using MRI.