Discontinuous stereotactic body radiotherapy schedule increases overall survival in early-stage non-small cell lung cancer.

OBJECTIVES: The duration of stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) may affect patient outcomes. We aimed to determine the impact of a continuous versus discontinuous SBRT schedule on local control (LC) and overall survival (OS) in NSCLC patients. MATERIALS AND METHODS: Consecutive NSCLC stage I patients (475) treated with SBRT in four centers were retrospectively analyzed. The delivered dose ranged from 48 to 75 Gy in 3-10 fractions. Based on the ratio between the treatment duration (TD) and number of fractions (n), patients were divided into two groups: continuous schedule (CS) (TD ≤ 1.6n; 239 patients) and discontinuous schedule (DS) (TD > 1.6n; 236 patients). LC and OS were compared using Cox regression analyses after propensity score matching (216 pairs). RESULTS: The median follow-up period was 41 months. Multivariate analysis showed that the DS (hazard ratio (HR): 0.42; 95 % confidence interval (CI): 0.22-0.78) and number of fractions (HR: 1.24; 95 % CI: 1.07-1.43) were significantly associated with LC. The DS (HR: 0.67; 95 % CI: 0.51-0.89), age (HR: 1.02; 95 % CI: 1-1.03), WHO performance status (HR: 2.27; 95 % CI: 1.39-3.7), and T stage (HR: 1.4; 95 % CI: 1.03-1.87) were significantly associated with OS. The 3-year LC and OS were 92 % and 64 % and 81 % and 53 % for DS and CS treatments, respectively (p < 0.01). Cox analysis confirmed that the discontinuous SBRT schedule significantly increased LC and OS. CONCLUSION: DS is associated with significantly improved LC and OS in early-stage NSCLC patients treated with SBRT.

Field output factors for small fields: A large multicentre study.

PURPOSE: The determination of output factors in small field dosimetry is a crucial point, especially when implementing stereotactic radiotherapy (SRT). Herein, a working group of the French medical physicist society (SFPM) was created to collect small field output factors. The objective was to gather and disseminate information on small field output factors based on different detectors for various clinical SRT equipment and measurement configurations. METHOD: Participants were surveyed for information about their SRT equipment, including the type of linear particle accelerator (linac), collimator settings, measurement conditions for the output factors and the detectors used. Participants had to report both the ratio of detector readings and the correction factors applied as described in the IAEA TRS-483 code of practice for nominal field sizes smaller or equal to 3 cm. Mean field output factors and their associated standard deviations were calculated when data from at least 3 linacs were available. RESULTS: 23 centres were enrolled in the project. Standard deviations of the mean field output factors were systematically smaller than 1.5% for field sizes larger or equal to 1 cm and reached 5% for the smallest field size (0.5 cm). Deviations with published data were smaller than 2% except for the 0.5 cm circular fixed aperture collimator of the CyberKnife where it reached 3.5%. CONCLUSION: These field output factor values obtained via a large multicentre study can be considered as an external cross verification for any radiotherapy centre starting a SRT program and should help minimize systematic errors when determining small field output factors.

ITV versus mid-ventilation for treatment planning in lung SBRT: a comparison of target coverage and PTV adequacy by using in-treatment 4D cone beam CT.

BACKGROUND: The internal target volume (ITV) approach and the mid-ventilation (MidV) concept are the two main respiratory motion-management strategies under free breathing. The purpose of this work was to compare the actual in-treatment target coverage during volumetric modulated arctherapy (VMAT) delivered through both ITV-based and MidV-based planning target volume (PTV) and to provide knowledge in choosing the optimal PTV for stereotactic body radiotherapy (SBRT) for lung lesions. METHODS AND MATERIALS: Thirty-two lung cancer patients treated by a VMAT technique were included in the study. For each fraction, the mean time-weighted position of the target was localized by using a 4-dimensional cone-beam CT (4D-CBCT)-based image guidance procedure. The respiratory-correlated location of the gross tumor volume (GTV) during treatment delivery was determined for each fraction by using in-treatment 4D-CBCT images acquired concurrently with VMAT delivery (4D-CBCTin-treat). The GTV was delineated from each of the ten respiratory phase-sorted 4D-CBCTin-treat datasets for each fraction. We defined target coverage as the average percentage of the GTV included within the PTV during the patient's breathing cycle averaged over the treatment course. Target coverage and PTVs were reported for a MidV-based PTV (PTVMidV) using dose-probabilistic margins and three ITV-based PTVs using isotropic margins of 5 mm (PTVITV + 5mm), 4 mm (PTVITV + 4mm) and 3 mm (PTVITV + 3mm). The in-treatment baseline displacements and target motion amplitudes were reported to evaluate the impact of both parameters on target coverage. RESULTS: Overall, 100 4D-CBCTin-treat images were analyzed. The mean target coverage was 98.6, 99.6, 98.9 and 97.2% for PTVMidV, PTVITV + 5mm, PTVITV + 4mm and PTVITV + 3mm, respectively. All the PTV margins led to a target coverage per treatment higher than 95% in at least 90% of the evaluated cases. Compared to PTVITV + 5mm, PTVMidV, PTVITV + 4mm and PTVITV + 3mm had mean PTV reductions of 16, 19 and 33%, respectively. CONCLUSION: When implementing VMAT with 4D-CBCT-based image guidance, an ITV-based approach with a tighter margin than the commonly used 5 mm margin remains an alternative to the MidV-based approach for reducing healthy tissue exposure in lung SBRT. Compared to PTVMidV, PTVITV + 3mm significantly reduced the PTV while still maintaining an adequate in-treatment target coverage.

[Reference bases of radiotherapy under stereotaxic conditions for bronchopulmonary, hepatic, prostatic, upper aero-digestive, cerebral and bone tumors or metastases]. / Bases référentielles de la radiothérapie en conditions stéréotaxiques pour les tumeurs ou métastases bronchopulmonaires, hépatiques, prostatiques, des voies aérodigestives supérieures, cérébrales et osseuses.

Since decades, stereotactic radiotherapy has spread out worldwide. Published results are very numerous. To clarify obviousness among all the publications, this recommendation review was written. Voluntarily, authors limited analysis of international best evidence literature on malignant tumors of lung, liver, prostate, head and neck, and metastasis of bone and brain. These data could be used to advance standardization and quality improvement of treatments performed in the nationwide radiotherapy departments and can provide useful guidance for centers worldwide.

Plan delivery quality assurance for CyberKnife: Statistical process control analysis of 350 film-based patient-specific QAs.

PURPOSE: Robotic radiosurgery requires plan delivery quality assurance (DQA) but there has never been a published comprehensive analysis of a patient-specific DQA process in a clinic. We proposed to evaluate 350 consecutive film-based patient-specific DQAs using statistical process control. We evaluated the performance of the process to propose achievable tolerance criteria for DQA validation and we sought to identify suboptimal DQA using control charts. METHODS AND MATERIAL: DQAs were performed on a CyberKnife-M6 using Gafchromic-EBT3 films. The signal-to-dose conversion was performed using a multichannel-correction and a scanning protocol that combined measurement and calibration in a single scan. The DQA analysis comprised a gamma-index analysis at 3%/1.5mm and a separate evaluation of spatial and dosimetric accuracy of the plan delivery. Each parameter was plotted on a control chart and control limits were calculated. A capability index (Cpm) was calculated to evaluate the ability of the process to produce results within specifications. RESULTS: The analysis of capability showed that a gamma pass rate of 85% at 3%/1.5mm was highly achievable as acceptance criteria for DQA validation using a film-based protocol (Cpm>1.33). 3.4% of DQA were outside a control limit of 88% for gamma pass-rate. The analysis of the out-of-control DQA helped identify a dosimetric error in our institute for a specific treatment type. CONCLUSION: We have defined initial tolerance criteria for DQA validations. We have shown that the implementation of a film-based patient-specific DQA protocol with the use of control charts is an effective method to improve patient treatment safety on CyberKnife.

CyberKnife® M6™: Peripheral dose evaluation for brain treatments.

PURPOSE: This study evaluates the peripheral dose (PD) delivered to healthy tissues for brain stereotactic radiotherapy treatments (SRT) performed with a CyberKnife M6™ Robotic Radiosurgery System and proposes a model to estimate PD before treatment. METHOD: PD was measured with thermoluminescent dosimeters. Measurements were performed to evaluate the influence of distance, collimator type (fixed or Iris™) and aperture size on PD for typical brain treatment plans simulated on an anthropomorphic phantom. A model to estimate PD was defined by fitting functions to these measurements. In vivo measurements were subsequently performed on 30 patients and compared to the model-predicted PD. RESULTS: PD (in cGy) was about 0.06% of MU at 15cm for a 20mm fixed collimator and 0.04% of MU for the same aperture with Iris™ collimator. In vivo measurements showed an average thyroid dose of 55mGy (σ=18.8mGy). Computed dose for thyroid, breast, umbilicus and gonads showed on average a relative difference of 3.4% with the in vivo dose (σ=12.4%). CONCLUSION: PD at the thyroid with Iris™ was about a third lower than with a fixed collimator in case of brain SRT. Despite uncertainties (use of anthropomorphic PD to estimate patient specific PD, surface PD to estimate OAR PD) the model allows PD to be estimated without in vivo measurements. This method could be used to optimise PD with different planning strategies.

Cx26 regulates proliferation of repairing basal airway epithelial cells.

The recovery of an intact epithelium following injury is critical for restoration of lung homeostasis, a process that may be altered in cystic fibrosis (CF). In response to injury, progenitor cells in the undamaged areas migrate, proliferate and re-differentiate to regenerate an intact airway epithelium. The mechanisms regulating this regenerative response are, however, not well understood. In a model of circular wound injury of well-differentiated human airway epithelial cell (HAEC) cultures, we identified the gap junction protein Cx26 as an important regulator of cell proliferation. We report that induction of Cx26 in repairing HAECs is associated with cell proliferation. We also show that Cx26 is expressed in a population of CK14-positive basal-like cells. Cx26 silencing in immortalized cell lines using siRNA and in primary HAECs using lentiviral-transduced shRNA enhanced Ki67-labeling index and Ki67 mRNA, indicating that Cx26 acts a negative regulator of HAEC proliferation. Cx26 silencing also markedly decreased the transcription of KLF4 in immortalized HAECs. We further show that CF HAECs exhibited deregulated expression of KLF4, Ki67 and Cx26 as well enhanced rate of wound closure in the early response to injury. These results point to an altered repair process of CF HAECs characterized by rapid but desynchronized initiation of HAEC activation and proliferation.

[Mid-ventilation position planning: optimal model for dose distribution in lung tumour]. / Planification selon la position moyenne du cycle respiratoire : modèle de planification optimale pour une distribution de dose dans les tumeurs pulmonaires.

PURPOSE: The dose distribution for lung tumour is estimated using a 3D-CT scan, and since a person breathes while the images are captured, the dose distribution doesn't reflect the reality. A 4D-CT scan integrates the motion of the tumour during breathing and, therefore, provides us with important information regarding tumour's motion in all directions, the motion volume (ITV) and the time-weighted average position (MVP). PATIENT AND METHODS: Based on these two concepts, we have estimated, for a lung carcinoma case a 3D dose distribution from a 3D-CT scan, and a 4D dose distribution from a 4-D CT scan. To this, we have applied a non-rigid registration to estimate the cumulative dose. RESULTS: Our study shows that the 4D dose estimation of the GTV is almost the same when made using MVP and ITV concepts, but sparring of the healthy lung is better done using the MPV model (MVP), as compared to the ITV model. This improvement of the therapeutic index allows, from a projection on the theoretical maximal dose to PTV (strictly restricted to doses for the lungs and the spinal cord), for an increase of about 11% on the total dose (maximal dose of 86 Gy for the ITV and 96 Gy for the MVP). CONCLUSION: Further studies with more patients are needed to confirm our data.

[Which IMRT? From "step and shoot" to VMAT: physicist point of view]. / Quelle RCMI? Du step and shoot au VMAT: point de vue du physicien.

Intensity-modulated radiation therapy (IMRT) is essential to have a dose distribution matching with the planning target volume (PTV) in case of concave-shape target. Today IMRT delivery techniques with linear accelerator can be divided into two classes: techniques with fixed gantry, called "step and shoot" (S&S) and "sliding window" (SW), and rotational techniques, called intensity modulated arc therapy (IMAT) and volumetric modulated arc therapy (VMAT). We discuss about constraints for IMRT implementation from dosimetric planning to treatment delivery. We compare S&S and VMAT performances concerning dose distribution quality, efficiency and delivery time. We describe quality controls that must be implemented and the methods for analysis and follow-up performances. VMAT tends to yield similar dose distribution to MRT with fixed gantry. VMAT also decreases monitor units as well as treatment delivery time to less than 5 minutes. However, VMAT is an IMRT technique more difficult to master than S&S technique because there are more variable parameters.

[High dose for prostate irradiation with image guided radiotherapy: contribution of intensity modulation arctherapy]. / Haute dose dans la prostate par radiothérapie guidée par l'image: apport de l'arcthérapie avec modulation d'intensité du faisceau.

PURPOSE: To compare two Intensity Modulated Radiation Therapy (IMRT) techniques for prostate cancer: the Volumetric Modulated Arc Therapy (VMAT) and the "Step and Shoot" technique (S&S). MATERIALS AND METHODS: VMAT and S&S plans (RX 18MV) were created and compared (Wilcoxon test) for 10 patients. The dosimetric goal of both treatments was to deliver 46 Gy to the seminal vesicles and 80 Gy to the prostate, while respecting the dose constrains in the organs at risk of toxicity. For one patient, the two techniques were compared for dose painting and escalation in target volumes defined on MRI and registered thanks to intraprostatic fiducials. RESULTS: VMAT, compared to S&S, offered: an increase of the PTV2s (prostate) volume receiving 77 to 80 Gy and a decrease of V(82) and V(83); a decrease of V(4) to V(6), V(16) to V(23), and V(69) to V(73) for the rectal wall; a decrease of V(25) for the bladder wall; a decrease of V(21) to V(43) for the femoral heads; a decrease of V(26) to V(44) and V(72) to V(80) but an increase of V(1) to V(21) and V(49) to V(60) for the healthy tissues. The Conformal Index "COIN" was better with VMAT than S&S (0.60 to 0.66). The delivered MU were significantly reduced with VMAT (8% mean) as well as the delivery time (4 min to 1.5 min). VMAT allowed delivering theorically 90Gy in the peripheral zone and 100 Gy in the tumor. CONCLUSION: In case of prostate irradiation, VMAT shows improvement compared with S&S. In particular, organs at risk are better spared, the delivery time is shortened and the number of delivered UM is decreased.