"Mid-P strategy" versus "internal target volume strategy in locally advanced non small cell lung cancer: Clinical results from the randomized non-comparative phase II study Mid-P.

BACKGROUND: Locally advanced non-small cell lung cancer (LA-NSCLC) reported poor 5-year survival rates with frequent local or regional recurrences. Personalized RT may contribute to improve control and clinical outcome. We investigated efficacy and tolerance of "Mid-position" (Mid-P) strategy versus the conventional Internal Target Volume (ITV) strategy in LA-NSCLC patients treated by definitive conformal radiotherapy. METHODS: This prospective non-comparative randomized monocentric phase II trial included adult patients with non-resected, non-metastatic, non-previously irradiated proven LA-NSCLC treated with definitive normo-fractionated conformal radiotherapy (+/- chemotherapy). Allocated patients (randomisation 2:1) were treated using Mid-P or ITV strategy. A Fleming single-stage design (1-sided α = 0.1, 80 % power, P0 = 30 %, P1 = 50 %) planned enrolment of 36 patients in the Mid-P group. The ITV group ensured the absence of selection bias. The primary outcome was 1-year progression-free- survival (1y-PFS) rate. RESULTS: Among 54 eligible patients included from September 2012 to May 2018, 51 patients were analyzed (Mid-P: N = 34; ITV: 17). The 1y-PFS was 38 % (1-sided 95 %CI 25 %-not reached) with Mid-P strategy, and 47 % (95 %CI [27 %-not reached[) with ITV. Loco-regional failure as first event mainly occurred within radiation-field regardless the strategy. Acute and middle-term radiation toxicities were observed with both strategies. CONCLUSION: Local control and survival remain poor using the Mid-P strategy in this prospective randomized non-comparative monocentric study investigating Mid-P strategy versus ITV strategy in LA-NSCLC. Since the Mid-P strategy is not integrated into routine software, and perceived as a time-consuming method, Mid-P strategy cannot be recommended in LA-NSCLCC treated by definitive normo-fractionated conformal radiotherapy outside clinical trials.

Multi-centre evaluation of variation in cumulative dose assessment in reirradiation scenarios.

BACKGROUND AND PURPOSE: Safe reirradiation relies on assessment of cumulative doses to organs at risk (OARs) across multiple treatments. Different clinical pathways can result in inconsistent estimates. Here, we quantified the consistency of cumulative dose to OARs across multi-centre clinical pathways. MATERIAL AND METHODS: We provided DICOM planning CT, structures and doses for two reirradiation cases: head & neck (HN) and lung. Participants followed their standard pathway to assess the cumulative physical and EQD2 doses (with provided α/ß values), and submitted DVH metrics and a description of their pathways. Participants could also submit physical dose distributions from Course 1 mapped onto the CT of Course 2 using their best available tools. To assess isolated impact of image registrations, a single observer accumulated each submitted spatially mapped physical dose for every participating centre. RESULTS: Cumulative dose assessment was performed by 24 participants. Pathways included rigid (n = 15), or deformable (n = 5) image registration-based 3D dose summation, visual inspection of isodose line contours (n = 1), or summation of dose metrics extracted from each course (n = 3). Largest variations were observed in near-maximum cumulative doses (25.4 - 41.8 Gy for HN, 2.4 - 33.8 Gy for lung OARs), with lower variations in volume/dose metrics to large organs. A standardised process involving spatial mapping of the first course dose to the second course CT followed by summation improved consistency for most near-maximum dose metrics in both cases. CONCLUSION: Large variations highlight the uncertainty in reporting cumulative doses in reirradiation scenarios, with implications for outcome analysis and understanding of published doses. Using a standardised workflow potentially including spatially mapped doses improves consistency in determination of accumulated dose in reirradiation scenarios.

Evaluation of a dedicated software for semi-automated VMAT planning of spine Stereotactic Body Radiotherapy (SBRT).

PURPOSE: To determine whether SBRT of spinal metastasis using a dedicated treatment planning system (TPS) and delivered with a gantry-based LINAC could provide plans of similar quality to the Cyberknife technology. Additional comparison was also done with other commercial TPS used for volumetric modulated arc therapy (VMAT) planning. MATERIALS AND METHODS: Thirty Spine SBRT patients, previously treated in our institution with CyberKnife (Accuray, Sunnyvale) using Multiplan TPS, were replanned in VMAT with an dedicated TPS (Elements Spine SRS, Brainlab, Munich) and our clinical TPS (Monaco, Elekta LTD, Stockholm), using exactly the same arc geometry. The comparison was done by assessing differences in dose delivered to PTV, CTV and spinal cord, calculating modulation complexity scores (MCS) and performing quality control (QA) of the plans. RESULTS: Regardless of the vertebra level, in general, no statistical difference was found in PTV coverage between all TPS. Conversely, PTV and CTV D50% were found significantly higher for the dedicated TPS compared to others. In addition, the dedicated TPS also resulted in better gradient index (GI) than clinical VMAT TPS, whatever the vertebral level, and better GI than Cyberknife TPS for the thoracic level only. The D2% to the spinal cord was generally significantly lower with the dedicated TPS compared with others. No significant difference was found in the MCS between both VMAT TPS. All QA were clinically acceptable. CONCLUSION: The Elements Spine SRS TPS offers very effective and user-friendly semi-automated planning tools and is secure and promising for gantry-based LINAC spinal SBRT.

Management of reirradiations: A clinical and technical overview based on a French survey.

INTRODUCTION: The reirradiation number increased due to systemic therapies and patient survival. Few guidelines regarding acceptable cumulative doses to organs at risk (OARs) and appropriate dose accumulation tools need, made reirradiation challenging. The survey objective was to present the French current technical and clinical practices in reirradiations. METHODS: A group of physician and physicists developed a survey gathering major issues of the topic. The questionnaire consisted in 4 parts: data collection, demographic, clinical and technical aspects. It was delivered through the SFRO and the SFPM. Data collection lasted 2 months and were gathered to compute statistical analysis. RESULTS: 48 institutions answered the survey. Difficulties about patient data collection were related to patient safety, administrative and technical limitations. Half of the institutions discussed reirradiation cases during a multidisciplinary meeting. It mainly aimed at discussing the indication and the new treatment total dose (92%). 79% of the respondents used various references but only 6% of them were specific to reirradiations. Patients with pain and clinical deficit were ranked as best inclusion criteria. 54.2% of the institutions considered OARs recovery, especially for spinal cord and brainstem. A commercial software was used for dose accumulation for 52% of respondents. Almost all institutions performed equivalent dose conversion (94%). A quarter of the institutions estimated not to have the appropriate equipment for reirradiation. CONCLUSION: This survey showed the various approaches and tools used in reirradiation management. It highlighted issues in collecting data, and the guidelines necessity for safe practices, to increase clinicians confidence in retreating patients.

Clinical outcomes and lung toxicities after lung SABR using dynamic conformal arc therapy: a single-institution cohort study.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is a validated treatment for early stage lung cancer and pulmonary metastases. It provides a high local control rate with low symptomatic toxicities. Recently, Dynamic Conformal Arc Therapy (DCAT), a delivery option that differs from conventional DCA, has been implemented in the Monaco Treatment Planning System for SABR. The aim of the study was to report clinical outcomes and toxicities for patients treated for lung SABR with this new technique. METHODS: We retrospectively identified adult patients treated for primary or secondary lung tumors with DCAT-SABR and reported their clinical, radiological, histological characteristics and dosimetric parameters. Total dose was delivered in 3 or 5 fractions for 95% of patients and prescribed on the 80% isodose line to the PTV periphery. RESULTS: 145 patients met inclusion criteria for a total of 152 lesions with a median follow up of 12 months. Local control for the irradiated site was 96.7% at 1 year. Overall survival was 93.1% at 1 year. Mean prescription dose in BED10 was 110 Gy. 92% of patients had a prescribed dose superior to 100 Gy BED10. Mean PTV coverage was 95.1%. There were 66 cases of grade 1 radiation pneumonitis (RP) (43%) and only 7 cases of symptomatic grade 2 RP (4.6%). CONCLUSION: Lung SABR for primary or metastatic lung tumors using dynamic conformal arc therapy provides efficient results of local control and low lung toxicities, similar to other SABR techniques. ADVANCES IN KNOWLEDGE: SABR using DCAT is a safe technique to treat lung lesions, allowing intra-fraction motion limitation, potentially higher OARs protection and a shortened beam delivery.

Harmonization of dose prescription for lung stereotactic radiotherapy.

Background and purpose: Pulmonary stereotactic treatments can be performed using dedicated linear accelerators as well as robotic-assisted units, and different strategies can be used for dose prescription. This study aimed to compare the doses received by the tumor with a gross tumor volume (GTV)-based prescription on D98%GTV using a robotic-assisted unit (method A) and planning target volume (PTV)-based prescription on D95%PTV using a dedicated linac (method B). Material & methods: Plans of 32 patients were collected for method A, and a dose of 3 × 18 Gy was prescribed using type A algorithm and recalculated using a Monte-Carlo (MC) algorithm. The plans were normalized to match D98%GTV with the mean D 98 % G T V ¯ of the cohort. The plans of 23 patients were collected for method B, and a dose of 3 × 18 Gy was prescribed to D95%PTV using a MC algorithm. A 4D-sum method was developed to estimate doses for PTV and GTV. For validation, all plans were recalculated using an independent MC double-check software. A dose harmonization on D98% GTV was determined for both methods. Results: For method A, mean doses were D2%GTV = 59.9 ± 2.1 Gy, D50%GTV = 55.6 ± 1.2 Gy, D98%GTV = 49.5 ± 0.0 Gy. For method B, the reported doses were D2%GTV = 64.6 ± 2.1 Gy, D50%GTV = 62.8 ± 1.7 Gy, and D98%GTV = 60.0 ± 1.7 Gy. The dose trade-off of D98%GTV = 55 Gy was obtained for both methods. For method A, it corresponded to a dose prescription of 3 × 20 Gy using type A algorithm, followed by rescaling to obtain D98%GTV = 55 Gy. For method B, it corresponded to a dose prescription of D95%PTV = 3 × 16.5 Gy using the MC algorithm. Conclusions: This study determined similar near-minimum doses D98% GTV of approximately 3 × 18.3 Gy (55 Gy) using a GTV-based prescription on a robotic-assisted unit (method A) and a PTV-based prescription on a dedicated linac (method B).

Toxicity and efficacy of stereotactic body radiotherapy for ultra-central lung tumours: a single institution real life experience.

OBJECTIVES: The use of stereotactic body radiotherapy (SBRT) to treat ultra-central lung tumours remains more controversial than for peripheral and central tumours. Our objective was to assess toxicities, local control (LC) rate and survival data in patients with ultra-central lung tumours treated with SBRT. METHODS: We conducted a retrospective and monocentric study about 74 patients with an ultra-central lung tumour, consecutively treated between 2012 and 2018. Ultra-central tumours were defined as tumours whose planning target volume overlapped one of the following organs at risk (OARs): the trachea, right and left main bronchi, intermediate bronchus, lobe bronchi, oesophagus, heart. RESULTS: Median follow-up was 25 months. Two patients (2.7%) showed Grade 3 toxicity. No Grade 4 or 5 toxicity was observed. 11% of patients experienced primary local relapse. LC rate was 96.7% at 1 year and 87.6% at 2 years. Median progression free survival was 12 months. Median overall survival was 31 months. CONCLUSION: SBRT for ultra-central tumours remains safe and effective as long as protecting organs at risk is treatment-planning priority. ADVANCES IN KNOWLEDGE: The present study is one of the rare to describe exclusively ultra-central tumours through real-life observational case reports. Globally, literature analysis reveals a large heterogeneity in ultra-central lung tumours definition, prescribed dose, number of fractions. In our study, patients treated with SBRT for ultra-central lung tumours experienced few Grade 3 toxicities (2.7%) and no Grade 4 or 5 toxicities, due to the highest compliance with dose constraints to OARs. LC remained efficient.

Brain metastases treated with hypofractionated stereotactic radiotherapy: 8 years experience after Cyberknife installation.

BACKGROUND: Hypofractionated stereotactic radiotherapy (HFSRT) is indicated for large brain metastases (BM) or proximity to critical organs (brainstem, chiasm, optic nerves, hippocampus). The primary aim of this study was to assess factors influencing BM local control after HFSRT. Then the effect of surgery plus HFSRT was compared with exclusive HFSRT on oncologic outcomes, including overall survival. MATERIALS AND METHODS: Retrospective study conducted in Léon Bérard Cancer Center, included patients over 18 years-old with BM, secondary to a tumor proven by histology and treated by HFSRT alone or after surgery. Three different dose-fractionation schedules were compared: 27 Gy (3 × 9 Gy), 30 Gy (5 × 6 Gy) and 35 Gy (5 × 7 Gy), prescribed on isodose 80%. Primary endpoint were local control (LC). Secondary endpoints were overall survival (OS) and radionecrosis (RN) rate. RESULTS: A total of 389 patients and 400 BM with regular MRI follow-up were analyzed. There was no statistical difference between the different dose-fractionations. On multivariate analysis, surgery (p = 0.049) and size (< 2.5 cm) (p = 0.01) were independent factors improving LC. The 12 months LC was 87.02% in the group Surgery plus HFSRT group vs 73.53% at 12 months in the group HFSRT. OS was 61.43% at 12 months in the group Surgery plus HFSRT group vs 50.13% at 12 months in the group HFSRT (p < 0.0085). Prior surgery (OR = 1.86; p = 0.0028) and sex (OR = 1.4; p = 0.0139) control of primary tumor (OR = 0.671, p = 0.0069) and KPS < 70 (OR = 0.769, p = 0.0094) were independently predictive of OS. The RN rate was 5% and all patients concerned were symptomatic. CONCLUSIONS: This study suggests that HFSRT is an efficient and well-tolerated treatment. The optimal dose-fractionation remains difficult to determine. Smaller size and surgery are correlated to LC. These results evidence the importance of surgery for larger BM (> 2.5 cm) with a poorer prognosis. Multidisciplinary committees and prospective studies are necessary to validate these observations.

Motion effects in proton treatments of hepatocellular carcinoma-4D robustly optimised pencil beam scanning plans versus double scattering plans.

Pencil beam scanning (PBS) proton therapy enables better dose conformality for complex anatomical geometries than passive proton scattering techniques, but is more susceptible to organ motion. This becomes an issue when treating moving tumours in the thorax or abdomen. Novel four-dimensional treatment planning approaches have been developed to increase the robustness of PBS plans against motion. However, their efficacy still needs to be examined by means of 4D dynamically accumulated dose (4DDD) analyses. This study investigates the potential use of 4D robust optimisation to maintain sufficient target coverage in the presence of organ motion, while sparing surrounding healthy tissue, for hepatocellular carcinoma (HCC). The liver is particularly suited to study motion interplay effects since the treatment region exhibits smaller density gradients and more homogeneous tissue than targets in the thorax, making it less prone to range errors. A facility-specific beam time model, developed and experimentally validated previously, was used for the clinical evaluation. 4DDD analyses of eleven target volumes did not show a significant improvement of the target coverage using 4D robust optimisation, but a reduction of the dose to close-by organs at risk. Interplay effects were averaged out for the applied fractionation scheme of 15 fractions. Contrary to PBS, passive double scattering (DS) plans yielded homogeneous 4DDD dose distributions in a single fraction. But, in some cases, they exceeded organ at risk dose limits, which were only satisfied in PBS. The average normal liver dose could be decreased by almost 6% compared to non-robustly optimised PBS plans and by 16% compared to DS plans when implementing 4D robust optimisation. Except for some very small tumours with large motion amplitudes, 4D robustly optimised PBS plans were found to be clinically acceptable even without supplementary motion mitigation techniques.

Patterns of locoregional failure in locally advanced non-small cell lung cancer treated with definitive conformal radiotherapy: Results from the Gating 2006 trial.

PURPOSE: To determine the patterns of locoregional failure (LRF) in patients with locally advanced non-small cell lung cancer treated with definitive radiotherapy (RT). PATIENTS AND METHODS: One hundred and fifty-four patients from the Gating 2006 prospective randomized trial were treated with conformal RT with or without respiratory motion management. For patients with a LRF as first event, treatment planning with simulation CT, pre-treatment 18FDG PET-CT and post-treatment images demonstrating recurrence were registered and analyzed. Measurable LRF was contoured (rGTV) and classified as in-field, marginal, or out-of-field. RESULTS: Median follow-up was 27.8 months. Forty-eight patients presented with LRF. One-year and 2-year locoregional disease-free survival rates were 77% (95% CI 70-83) and 72% (95% CI 64-79) respectively. 79% of the patients with LRF as first event relapsed within the RT field (55% isolated), 30% had marginal LRF component. Isolated out-of-field failure occurred in only 3% of all patients. The regions of highest FDG-uptake on pre-treatment PET-CT were located within the recurrence in 91% of patients with in-field LRF. CONCLUSION: In-field failure was the most common pattern of failure. Escalated dose RT with high-dose fractions guided by PET parameters warrants further investigation.

Deformable image registration applied to lung SBRT: Usefulness and limitations.

Radiation therapy (RT) of the lung requires deformation analysis. Deformable image registration (DIR) is the fundamental method to quantify deformations for various applications: motion compensation, contour propagation, dose accumulation, etc. DIR is therefore unavoidable in lung RT. DIR algorithms have been studied for decades and are now available both within commercial and academic packages. However, they are complex and have limitations that every user must be aware of before clinical implementation. In this paper, the main applications of DIR for lung RT with their associated uncertainties and their limitations are reviewed.

Inverse treatment planning for spinal robotic radiosurgery: an international multi-institutional benchmark trial.

Stereotactic radiosurgery (SRS) is the accurate, conformal delivery of high-dose radiation to well-defined targets while minimizing normal structure doses via steep dose gradients. While inverse treatment planning (ITP) with computerized optimization algorithms are routine, many aspects of the planning process remain user-dependent. We performed an international, multi-institutional benchmark trial to study planning variability and to analyze preferable ITP practice for spinal robotic radiosurgery. 10 SRS treatment plans were generated for a complex-shaped spinal metastasis with 21 Gy in 3 fractions and tight constraints for spinal cord (V14Gy < 2 cc, V18Gy < 0.1 cc) and target (coverage > 95%). The resulting plans were rated on a scale from 1 to 4 (excellent-poor) in five categories (constraint compliance, optimization goals, low-dose regions, ITP complexity, and clinical acceptability) by a blinded review panel. Additionally, the plans were mathemati-cally rated based on plan indices (critical structure and target doses, conformity, monitor units, normal tissue complication probability, and treatment time) and compared to the human rankings. The treatment plans and the reviewers' rankings varied substantially among the participating centers. The average mean overall rank was 2.4 (1.2-4.0) and 8/10 plans were rated excellent in at least one category by at least one reviewer. The mathematical rankings agreed with the mean overall human rankings in 9/10 cases pointing toward the possibility for sole mathematical plan quality comparison. The final rankings revealed that a plan with a well-balanced trade-off among all planning objectives was preferred for treatment by most par-ticipants, reviewers, and the mathematical ranking system. Furthermore, this plan was generated with simple planning techniques. Our multi-institutional planning study found wide variability in ITP approaches for spinal robotic radiosurgery. The participants', reviewers', and mathematical match on preferable treatment plans and ITP techniques indicate that agreement on treatment planning and plan quality can be reached for spinal robotic radiosurgery.

Is abdominal compression useful in lung stereotactic body radiation therapy? A 4DCT and dosimetric lobe-dependent study.

PURPOSE: To determine the usefulness of abdominal compression in lung stereotactic body radiation therapy (SBRT) depending on lobe tumor location. MATERIALS AND METHODS: Twenty-seven non-small cell lung cancer patients were immobilized in the Stereotactic Body Frame™ (Elekta). Eighteen tumors were located in an upper lobe, one in the middle lobe and nine in a lower lobe (one patient had two lesions). All patients underwent two four-dimensional computed tomography (4DCT) scans, with and without abdominal compression. Three-dimensional tumor motion amplitude was determined using manual landmark annotation. We also determined the internal target volume (ITV) and the influence of abdominal compression on lung dose-volume histograms. RESULTS: The mean reduction of tumor motion amplitude was 3.5 mm (p = 0.009) for lower lobe tumors and 0.8 mm (p = 0.026) for upper/middle lobe locations. Compression increased tumor motion in 5 cases. Mean ITV reduction was 3.6 cm(3) (p = 0.039) for lower lobe and 0.2 cm(3) (p = 0.048) for upper/middle lobe lesions. Dosimetric gain of the compression for lung sparing was not clinically relevant. CONCLUSIONS: The most significant impact of abdominal compression was obtained in patients with lower lobe tumors. However, minor or negative effects of compression were reported for other patients and lung sparing was not substantially improved. At our institute, patients with upper or middle lobe lesions are now systematically treated without compression and the usefulness of compression for lower lobe tumors is evaluated on an individual basis.

Nonrigid registration method to assess reproducibility of breath-holding with ABC in lung cancer.

PURPOSE: To study the interfraction reproducibility of breath-holding using active breath control (ABC), and to develop computerized tools to evaluate three-dimensional (3D) intrathoracic motion in each patient. METHODS AND MATERIALS: Since June 2002, 11 patients with non-small-cell lung cancer enrolled in a Phase II trial have undergone four CT scans: one during free-breathing (reference) and three using ABC. Patients left the room between breath-hold scans. The patient's breath was held at the same predefined phase of the breathing cycle (about 70% of the vital capacity) using the ABC device, then patients received 3D-conformal radiotherapy. Automated computerized tools for breath-hold CT scans were developed to analyze lung and tumor interfraction residual motions with 3D nonrigid registration. RESULTS: All patients but one were safely treated with ABC for 7 weeks. For 6 patients, the lung volume differences were <5%. The mean 3D displacement inside the lungs was between 2.3 mm (SD 1.4) and 4 mm (SD 3.3), and the gross tumor volume residual motion was 0.9 mm (SD 0.4) to 5.9 mm (SD 0.7). The residual motion was slightly greater in the inferior part of the lung than the superior. For 2 patients, we detected volume changes >300 cm(3) and displacements >10 mm, probably owing to atelectasia and emphysema. One patient was excluded, and two others had incomplete data sets. CONCLUSION: Breath-holding with ABC was effective in 6 patients, and discrepancies were clinically accountable in 2. The proposed 3D nonrigid registration method allows for personalized evaluation of breath-holding reproducibility with ABC. It will be used to adapt the patient-specific internal margins.