[Does radiation therapy for prostate cancer increase the risk of second cancers?] / La radiothérapie du cancer de la prostate augmente-t-elle le risque de seconds cancers ?

PURPOSE: The increased risk of second cancer after prostate radiotherapy is a debated clinical concern. The objective of the study was to assess the risk of occurrence of second cancers after prostate radiation therapy based on the analysis the literature, and to identify potential factors explaining the discrepancies in results between studies. MATERIALS AND METHODS: A review of the literature was carried out, comparing the occurrence of second cancers in patients all presenting with prostate cancer, treated or not by radiation. RESULTS: This review included 30 studies reporting the occurrence of second cancers in 2,112,000 patients treated or monitored for localized prostate cancer, including 1,111,000 by external radiation therapy and 103,000 by brachytherapy. Regarding external radiation therapy, the average follow-up was 7.3years. The majority of studies (80%) involving external radiation therapy, compared to no external radiation therapy, showed an increased risk of second cancers with a hazard ratio ranging from 1.13 to 4.9, depending on the duration of the follow-up. The median time to the occurrence of these second cancers after external radiotherapy ranged from 4 to 6years. An increased risk of second rectal and bladder cancer was observed in 52% and 85% of the studies, respectively. Considering a censoring period of more than 10 years after irradiation, 57% and 100% of the studies found an increased risk of rectal and bladder cancer, without any impact in overall survival. Studies of brachytherapy did not show an increased risk of second cancer. However, these comparative studies, most often old and retrospective, had many methodological biases. CONCLUSION: Despite numerous methodological biases, prostate external radiation therapy appears associated with a moderate increase in the risk of second pelvic cancer, in particular bladder cancer, without impacting survival. Brachytherapy does not increase the risk of a second cancer.

Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial.

BACKGROUND: To evaluate potential synergistic effect of pembrolizumab with radiotherapy (RT) compared with a standard-of-care (SOC) cetuximab-RT in patients with locally advanced-squamous cell carcinoma of head and neck (LA-SCCHN). PATIENTS AND METHODS: Patients with nonoperated stage III-IV SCC of oral cavity, oropharynx, hypopharynx, and larynx and unfit for receiving high-dose cisplatin were enrolled. Patients received once-daily RT up to 69.96 Gy in 33 fractions with weekly cetuximab (cetuximab-RT arm) or 200 mg Q3W pembrolizumab during RT (pembrolizumab-RT arm). The primary endpoint was locoregional control (LRC) rate 15 months after RT. To detect a difference between arms of 60%-80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at two-sided significance level of 0.20. RESULTS: Between May 2016 and October 2017, 133 patients were randomized to cetuximab-RT (n = 66) and pembrolizumab-RT (n = 67). Two patients (one in each arm) were not included in the analysis (a consent withdrawal and a progression before treatment start). The median age was 65 years (interquartile range 60-70 years), 92% were smokers, 60% were oropharynx (46% of oropharynx with p16+) and 75% were stage IV. Median follow-up was 25 months in both arms. The 15-month LRC rate was 59% with cetuximab-RT and 60% with pembrolizumab-RT ]odds ratio 1.05, 95% confidence interval (CI) 0.43-2.59; P = 0.91]. There was no significant difference between arms for progression-free survival (hazard ratio 0.85, 95% CI 0.55-1.32; P = 0.47) and for overall survival (hazard ratio 0.83, 95% CI 0.49-1.40; P = 0.49). Toxicity was lower in the pembrolizumab-RT arm than in the cetuximab-RT arm: 74% versus 92% patients with at least one grade ≥3 adverse events (P = 0.006), mainly due to mucositis, radiodermatitis, and rash. CONCLUSION: Compared with the SOC cetuximab-RT, pembrolizumab concomitant with RT did not improve the tumor control and survival but appeared less toxic in unfit patients with LA-SCCHN.

A high-performance method of deep learning for prostate MR-only radiotherapy planning using an optimized Pix2Pix architecture.

PURPOSE: The first aim was to generate and compare synthetic-CT (sCT) images using a conditional generative adversarial network (cGAN) method (Pix2Pix) for MRI-only prostate radiotherapy planning by testing several generators, loss functions, and hyper-parameters. The second aim was to compare the optimized Pix2Pix model with five other architectures (bulk-density, atlas-based, patch-based, U-Net, and GAN). METHODS: For 39 patients treated by VMAT for prostate cancer, T2-weighted MRI images were acquired in addition to CT images for treatment planning. sCT images were generated using the Pix2Pix model. The generator, loss function, and hyper-parameters were tuned to improve sCT image generation (in terms of imaging endpoints). The final evaluation was performed by 3-fold cross-validation. This method was compared to five other methods using the following imaging endpoints: the mean absolute error (MAE) and mean error (ME) between sCT and reference CT images (rCT) of the whole pelvis, bones, prostate, bladder, and rectum. For dose planning analysis, the dose-volume histogram metric differences and 3D gamma analysis (local, 1 %/1 mm) were calculated using the sCT and reference CT images. RESULTS: Compared with the other architectures, Pix2Pix with Perceptual loss function and generator ResNet 9 blocks showed the lowest MAE (29.5, 107.7, 16.0, 13.4, and 49.1 HU for the whole pelvis, bones, prostate, bladder, and rectum, respectively) and the highest gamma passing rates (99.4 %, using the 1 %/1mm and 10 % dose threshold criterion). Concerning the DVH points, the mean errors were -0.2% for the planning target volume V95%, 0.1 % for the rectum V70Gy, and -0.1 % for the bladder V50Gy. CONCLUSION: The sCT images generated from MRI data with the Pix2Pix architecture had the lowest image errors and similar dose uncertainties (in term of gamma pass-rate and dose-volume histogram metric differences) than other deep learning methods.

Role of radiotherapy in the treatment of primary vaginal cancer: Recommendations of the French society for radiation oncology.

Primary vaginal cancers are rare tumours, for which external beam radiotherapy and brachytherapy are major treatment tools. Given the complexity of brachytherapy techniques, the treatment should be performed in specialised centres. We present the recommendations of the French society for radiation oncology on the indications and techniques for external beam radiotherapy and brachytherapy for primary vaginal cancer.

Radiotherapy of cervical cancer.

External beam radiotherapy and brachytherapy are major treatments in the management of cervical cancer. For early-stage tumours with local risk factors, brachytherapy is a preoperative option. Postoperative radiotherapy is indicated according to histopathological criteria. For advanced local tumours, chemoradiation is the standard treatment, followed by brachytherapy boost, which is not optional. We present the update of the recommendations of the French Society of Oncological Radiotherapy on the indications and techniques for external beam radiotherapy and brachytherapy for cervical cancer.

Radiotherapy for endometrial cancer.

The first intent upfront treatment of endometrial cancer is surgery. External radiotherapy and brachytherapy; however, are important tools in adjuvant setting, according to histopathological risk factors for locoregional recurrence or in the event of an inoperable tumor. We present the update of the recommendations of the French society of oncological radiotherapy on the indications and technical methods of performing radiotherapy and brachytherapy for endometrial cancer.

Image-guided radiotherapy.

We present the updated recommendations of the French society for oncological radiotherapy on image-guided radiotherapy (IGRT). The objective of the IGRT is to take into account the anatomical variations of the target volume occurring between or during the irradiation fractions, such as displacements and/or deformations, so that the delivered dose corresponds to the planned dose. This article presents the different IGRT devices, their use and quality control, and quantify the possible additional dose generated by each of them. The practical implementation of IGRT in various tumour locations is summarised, from the different "RecoRad™" guideline articles. Adaptive radiotherapy is then detailed, due to its complexity and its probable development in the next years. The place of radiation technologist in the practice of IGRT is then specified. Finally, a brief update is proposed on the delicate question of the additional dose linked to the in-room imaging, which must be estimated and documented at a minimum, as long as it is difficult to integrate it into the calculation of the dose distribution.

Role of radiotherapy in the management of vulvar cancer: Recommendations of the French society for radiation oncology.

Primary vulvar carcinomas are rare gynaecological cancers, for which surgery is the mainstay of treatment. There is however a major place for external beam radiotherapy in the situation of inoperable locally advanced tumours and/or as adjuvant therapy, when there are risk factors for locoregional relapse. We present the recommendations of the French society for radiation oncology on the indications and techniques for radiotherapy in the treatment of primary vulvar cancer.

Deep learning methods to generate synthetic CT from MRI in radiotherapy: A literature review.

PURPOSE: In radiotherapy, MRI is used for target volume and organs-at-risk delineation for its superior soft-tissue contrast as compared to CT imaging. However, MRI does not provide the electron density of tissue necessary for dose calculation. Several methods of synthetic-CT (sCT) generation from MRI data have been developed for radiotherapy dose calculation. This work reviewed deep learning (DL) sCT generation methods and their associated image and dose evaluation, in the context of MRI-based dose calculation. METHODS: We searched the PubMed and ScienceDirect electronic databases from January 2010 to March 2021. For each paper, several items were screened and compiled in figures and tables. RESULTS: This review included 57 studies. The DL methods were either generator-only based (45% of the reviewed studies), or generative adversarial network (GAN) architecture and its variants (55% of the reviewed studies). The brain and pelvis were the most commonly investigated anatomical localizations (39% and 28% of the reviewed studies, respectively), and more rarely, the head-and-neck (H&N) (15%), abdomen (10%), liver (5%) or breast (3%). All the studies performed an image evaluation of sCTs with a diversity of metrics, with only 36 studies performing dosimetric evaluations of sCT. CONCLUSIONS: The median mean absolute errors were around 76 HU for the brain and H&N sCTs and 40 HU for the pelvis sCTs. For the brain, the mean dose difference between the sCT and the reference CT was <2%. For the H&N and pelvis, the mean dose difference was below 1% in most of the studies. Recent GAN architectures have advantages compared to generator-only, but no superiority was found in term of image or dose sCT uncertainties. Key challenges of DL-based sCT generation methods from MRI in radiotherapy is the management of movement for abdominal and thoracic localizations, the standardization of sCT evaluation, and the investigation of multicenter impacts.

[How a self-managed team can improve cohesion and communication during the patient's journey in a radiotherapy department: Experience of centre Jean-Bernard (Le Mans, France)]. / Comment une équipe autonome peut améliorer la cohésion et la communication autour de la prise en charge du patient en radiothérapie : expérience du centre Jean-Bernard.

Efficient communication between professionals is of upmost importance in improving treatment safety in a radiotherapy department, and is also necessary to enhance the quality of work life. Taking as example the organizations in industry, a self-managed team centred on patients with head and neck cancers treated with radiation has been implemented in 2018 in centre Jean-Bernard (Le Mans, France). After over a year's experience, a real benefice has been found and validates the plan to extend this model to other departments.

Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study.

BACKGROUND: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. PATIENTS AND METHODS: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. RESULTS: Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72-1.08; P = 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85-1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9-43.1), 30.4% (24.7-36.3), and 30.5% (24.7-36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. CONCLUSION: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02369874.

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.

Implementation of an optimization method for parotid gland sparing during inverse planning for head and neck cancer radiotherapy.

PURPOSE: To guide parotid gland (PG) sparing at the dose planning step, a specific model based on overlap between PTV and organ at risk (Moore et al.) was developed and evaluated for VMAT in head-and-neck (H&N) cancer radiotherapy. MATERIALS AND METHODS: One hundred and sixty patients treated for locally advanced H&N cancer were included. A model optimization was first performed (20 patients) before a model evaluation (110 patients). Thirty cases were planned with and without the model to quantify the PG dose sparing. The inter-operator variability was evaluated on one case, planned by 12 operators with and without the model. The endpoints were PG mean dose (Dmean), PTV homogeneity and number of monitor units (MU). RESULTS: The PG Dmean predicted by the model was reached in 89% of cases. Using the model significantly reduced the PG Dmean: -6.1±4.3Gy. Plans with the model showed lower PTV dose homogeneity and more MUs (+10.5% on average). For the inter-operator variability, PG dose volume histograms without the optimized model were significantly different compared to those with the model; the Dmean standard deviation for the ipsilateral PG decreased from 2.2Gy to 1.2Gy. For the contralateral PG, this value decreased from 2.9Gy to 0.8Gy. CONCLUSION: During the H&N inverse planning, the optimized model guides to the lowest PG achievable mean dose, allowing a significant PG mean dose reduction of -6.1Gy. Integrating this method at the treatment-planning step significantly reduced the inter-patient and inter-operator variabilities.

Towards large scale orientation mapping using the eCHORD method.

eCHORD is an alternative method for orientation mapping in Scanning Electron Microscopy that involves channeling contrast observed in BSE images. The sample tilt being small (10°), eCHORD could be a promising method for large scale maps as it limits the image deformation sometimes observed with EBSD maps. However, when the magnification is low, the scan deflection of the beam becomes important, which may modify the channeling conditions of analyzed grains, leading to orientation errors. A correction method for the resulting orientations is proposed and a resulting map on a Si single crystal is presented with an experimental misorientation of 0.12° across a field of view of 2.3 × 1.7 mm2.

Angular resolution expected from iCHORD orientation maps through a revisited ion channeling model.

Crystalline orientation maps are obtained in a Focused Ion Beam (FIB) microscope using the ion CHanneling ORientation Determination (iCHORD) method, which relies on the channeling phenomenon observed in ion-induced secondary electron images. The current paper focuses on the angular resolution that can be expected from such orientation maps, obtained using a revisited ion channeling model. A specific procedure was developed to evaluate the angular resolution, based on the distribution of orientation errors when evaluating controlled sample disorientation. The main advantage is that no external reference is required. An angular resolution of 1° is obtained on a nickel based sample using standard acquisition conditions. This value fulfills most of the needs in terms of microstructural characterization usually carried out by Electron Back Scattered Diffraction.

A density assignment method for dose monitoring in head-and-neck radiotherapy.

BACKGROUND AND PURPOSE: During head-and-neck (H&N) radiotherapy, the parotid glands (PGs) may be overdosed; thus, a tool is required to monitor the delivered dose. This study aimed to assess the dose accuracy of a patient-specific density assignment method (DAM) for dose calculation to monitor the dose to PGs during treatment. PATIENTS AND METHODS: Forty patients with H&N cancer received an intensity modulated radiation therapy (IMRT), among whom 15 had weekly CTs. Dose distributions were calculated either on the CTs (CTref), on one-class CTs (1C-CT, water), or on three-class CTs (3C-CT, water-air-bone). The inter- and intra-patient DAM uncertainties were evaluated by the difference between doses calculated on CTref and 1C-CTs or 3C-CTs. PG mean dose (Dmean) and spinal cord maximum dose (D2%) were considered. The cumulated dose to the PGs was estimated by the mean Dmean of the weekly CTs. RESULTS: The mean (maximum) inter-patient DAM dose uncertainties for the PGs (in cGy) were 23 (75) using 1C-CTs and 12 (50) using 3C-CTs (p ≤ 0.001). For the spinal cord, these uncertainties were 118 (245) and 15 (67; p ≤ 0.001). The mean (maximum) DAM dose uncertainty between cumulated doses calculated on CTs and 3C-CTs was 7 cGy (45 cGy) for the PGs. Considering the difference between the planned and cumulated doses, 53% of the ipsilateral and 80% of the contralateral PGs were overdosed by +3.6 Gy (up to 8.2 Gy) and +1.9 Gy (up to 5.2 Gy), respectively. CONCLUSION: The uncertainty of the three-class DAM appears to be clinically non-significant (<0.5 Gy) compared with the PG overdose (up to 8.2 Gy). This DAM could therefore be used to monitor PG doses and trigger replanning.

[Siriade 2.0: An e-learning platform for radiation oncology contouring]. / Siriade 2.0 : outil de formation en ligne à la délinéation en radiothérapie.

PURPOSE: In 2008, the French national society of radiation oncology (SFRO) and the association for radiation oncology continued education (AFCOR) created Siriade, an e-learning website dedicated to contouring. MATERIAL AND METHODS: Between 2015 and 2017, this platform was updated using the latest digital online tools available. Two main sections were needed: a theoretical part and another section of online workshops. RESULTS: Teaching courses are available as online commented videos, available on demand. The practical section of the website is an online contouring workshop that automatically generates a report quantifying the quality of the user's delineation compared with the experts'. CONCLUSION: Siriade 2.0 is an innovating digital tool for radiation oncology initial and continuous education.

Adaptive radiotherapy for head and neck cancer.

INTRODUCTION: Large anatomical variations can be observed during the treatment course intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC), leading to potential dose variations. Adaptive radiotherapy (ART) uses one or several replanning sessions to correct these variations and thus optimize the delivered dose distribution to the daily anatomy of the patient. This review, which is focused on ART in the HNC, aims to identify the various strategies of ART and to estimate the dosimetric and clinical benefits of these strategies. MATERIAL AND METHODS: We performed an electronic search of articles published in PubMed/MEDLINE and Science Direct from January 2005 to December 2016. Among a total of 134 articles assessed for eligibility, 29 articles were ultimately retained for the review. Eighteen studies evaluated dosimetric variations without ART, and 11 studies reported the benefits of ART. RESULTS: Eight in silico studies tested a number of replanning sessions, ranging from 1 to 6, aiming primarily to reduce the dose to the parotid glands. The optimal timing for replanning appears to be early during the first two weeks of treatment. Compared to standard IMRT, ART decreases the mean dose to the parotid gland from 0.6 to 6 Gy and the maximum dose to the spinal cord from 0.1 to 4 Gy while improving target coverage and homogeneity in most studies. Only five studies reported the clinical results of ART, and three of those studies included a non-randomized comparison with standard IMRT. These studies suggest a benefit of ART in regard to decreasing xerostomia, increasing quality of life, and increasing local control. Patients with the largest early anatomical and dose variations are the best candidates for ART. CONCLUSION: ART may decrease toxicity and improve local control for locally advanced HNC. However, randomized trials are necessary to demonstrate the benefit of ART before using the technique in routine practice.

[Organization and risk management in stereotaxic body radiotherapy at the treatment station]. / Organisation et gestion des risques en radiothérapie stéréotaxique au poste de traitement.

The development of stereotaxic body radiotherapy in the last decade has forced the radiotherapy departments to redouble their efforts in the fields of quality and risk management. For this purpose, increasingly complex and rigorous controls of high performance machines as well as a solid team training must be put in place. Extreme hypofractionation requires both increased vigilance at the treatment desk and well-defined and known procedures. The in place organizations contribute to the control of the risks related to the stereotaxic body radiotherapy machines. The medical presence at the beginning of the treatment fractions has been specified as mandatory in a regulatory way since January 2017. This not only ensures security, but also transmits information to the radiation therapy technicians. At the Eugène-Marquis center, the skills of the technicians for stereotaxic body radiotherapy on two dedicated machines (Cyberknife® and Versa HD® Novalis® type) have been upgraded. An accreditation is formalized after a training period and re-evaluated annually. The communication inside and outside the radiotherapy field plays also an important role in maintaining a high level of exchange and sharing of essential information. The means implemented at the Eugène-Marquis center increase the risk control of SBRT, by paying attention to the management of skills at the treatment station.