Multicriteria optimization of radiation therapy: Towards empowerment and standardization of reverse planning for head and neck squamous cell carcinoma.

PURPOSE: The purpose of this study was to assess if multicriteria optimization could limit interoperator variability in radiation therapy planning and assess if this method could contribute to target volume coverage and sparing of organ at risk for intensity-modulated curative radiation therapy of head and neck cancers. MATERIAL AND METHODS: We performed a retrospective analysis on 20 patients treated for an oropharyngeal or oral cavity squamous cell carcinoma. We carried out a comparative dosimetric study of manual plans produced with Precision® software, compared with the plans proposed using the multicriteria optimization method (RayStation®). We assessed interoperator reproducibility on the first six patients, and dosimetric contribution in sparing organs at risk using the multicriteria optimization method. RESULTS: Median age was 69 years, most lesions were oropharyngeal carcinoma (65%), and 35% lesions were stage T3. First, we obtained a high degree of similarity between the four operator measurements for each patient at the level of each organ. Intraclass correlation coefficients were greater than 0.85. Second, we observed a significant dosimetric benefit for contralateral parotid gland, homolateral and contralateral masseter muscles, homolateral and contralateral pterygoid muscles and for the larynx (P<0.05). For the contralateral parotid gland, the mean dose difference between the multicriteria optimization and manual plans was -2.0Gy (P=0.01). Regarding the larynx, the mean dose difference between the two plans was -4.6Gy (P<0.001). CONCLUSION: Multicriteria optimization is a reproducible technique and faster than manual optimization. It allows dosimetric advantages on organs at risk, especially for those not usually taken into consideration in manual dosimetry. This may lead to improved quality of life.

[Proposal for the delineation of postoperative primary clinical target volumes in maxillary sinus and nasal cavity cancers]. / Proposition de délinéation des volumes cibles anatomocliniques postopératoires de la tumeur primitive des cancers du sinus maxillaire et des cavités nasales.

In this article, we propose a consensus delineation of postoperative clinical target volumes for the primary tumour in maxillary sinus and nasal cavity cancers. These guidelines are developed based on radioanatomy and the natural history of those cancers. They require the fusion of the planning CT with preoperative imaging for accurate positioning of the initial GTV and the combined use of the geometric and anatomical concepts for the delineation of clinical target volume for the primary tumour. This article does not discuss the indications of external radiotherapy (nor concurrent systemic treatment) but focuses on target volumes when there is an indication for radiotherapy.

[Real world data in radiotherapy: A data farming project by Unitrad]. / Données de vie réelle en radiothérapie : le data farming du groupe Unitrad.

The aim of the data farming project by the Unitrad group is to produce and use large quantities of structured real-life data throughout radiotherapy treatment. Starting in 2016, target real world data were selected at expert consensus conferences and regularly updated, then captured in MOSAIQ© as the patient was treated. For each partner institution, the data was then stored in a relational database, then extracted and used by researchers to create real world knowledge. This production was carried out in a multicentre, coordinated fashion. When necessary, the raw data was shared according to the research projects, in compliance with regulations. Feedack was provided at each stage, enabling the system to evolve flexibly and rapidly, using the "agile" method. This work, which is constantly evolving, has led to the creation of health data warehouses focused on data of interest in radiotherapy, and the publication of numerous academic studies. It forms part of the wider context of the exploitation of real-life data in cancerology. Unitrad data farming is a collaborative project for creating knowledge from real-life radiotherapy data, based on an active network of clinicians and researchers.

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.

Histosurgical mapping of endoscopic endonasal surgery of sinonasal tumours to improve radiotherapy guidance.

PURPOSE: Endoscopic endonasal surgery (EES) is becoming a standard for most malignant sinonasal tumours. Margin analysis after piecemeal resection is complex and optimally relies on accurate histosurgical mapping. Postoperative radiotherapy may be adapted based on margin assessment mapping to reduce the dose to some sinonasal subvolumes. We assessed the use of histosurgical mapping by radiation oncologists (RO). MATERIAL AND METHODS: A French practice survey was performed across 29 ENT expert RO (2 did not answer) regarding integration of information on EES, as well as quality of operative and pathology reportsto refine radiotherapy planning after EES. This was assessed through an electronic questionnaire. RESULTS: EES was ubiquitously performed in France. Operative and pathology reports yielded accurate description of EES samples according to 66.7% of interviewed RO. Accuracy of margin assessment was however insufficient according to more than 40.0% of RO. Additional margins/biopsies of the operative bed were available in 55.2% (16/29) of the centres. In the absence of additional margins, quality of resection after EES was considered as microscopically incomplete in 48.3% or dubious in 48.3% of RO. As performed, histosurgical mapping allowed radiotherapy dose and volumes adaptation according to 26.3% of RO only. CONCLUSIONS: Standardized histosurgical mapping with margin and additional margin analysis could be more systematic. Advantages of accurate EES reporting could be dose painting radiotherapy to further decrease morbidity in sinonasal tumours.

[Radiotherapy for patients with early-stage glottic squamous cell carcinoma of the larynx: Interest of hypofractionation?] / Radiothérapie du carcinome épidermoïde du larynx de stade précoce, étage glottique : intérêt de l'hypofractionnement ?

Hypofractionated radiotherapy of early-stage squamous cell carcinoma of the glottic larynx is a promising treatment option. This can be divided into radiotherapy with moderate hypofractionation (up to 2.5Gy per fraction), more intense hypofractionation (between 2.5 and 4.5Gy per fraction) and stereotactic radiotherapy (above 4.5Gy per fraction). Most studies evaluating moderate hypofractionation show a local control rate between 85 and 95%. Acute laryngeal toxicity is superior to conventional treatment, but only for grades 1 and 2, with no significant difference reported for severe toxicity. Stereotactic radiotherapy in this pathology is also an emerging entity, but some authors have reported significant toxicity. There are currently no standardized guidelines for treatment and management regimen. We conducted a systemic review of published prospective and retrospective trials to evaluate efficacy, toxicity, and discuss future directions.

Flap delineation guidelines in postoperative head and neck radiation therapy for head and neck cancers.

INTRODUCTION: Reconstructive surgery in head and neck cancers frequently involves the use of autologous flaps to improve functional outcomes. However, the literature suggests that postoperative radiotherapy deteriorates functional outcomes due to flap atrophy and fibrosis. Data on patterns of relapse after postoperative radiotherapy with a flap are lacking, resulting in heterogenous delineation of postoperative clinical target volumes (CTV). Flap delineation is unusual in routine practice and there are no guidelines on how to delineate flaps. Therefore, we aim to propose a guideline for flap delineation in head and neck cancers to assess dose-effects more accurately with respect to flaps. MATERIAL AND METHODS: Common flaps were selected. They were delineated by radiation oncologists and head and neck surgeons based on operative reports, on contrast-enhanced planning CTs and checked by a radiologist. Each flap was divided into its vascular pedicle and its soft tissue components (fat, fascia/ muscle, skin, bone). RESULTS: Delineation (body and pedicle) of Facial Artery Musculo-Mucosal, pectoralis, radial forearm, anterolateral thigh, fibula and scapula flaps was performed. Based on information provided in operative reports, i.e. tissue components, size and location, flaps can be identified. The various tissue components of each flap can be individualized to facilitate the delineation. CONCLUSION: This atlas could serve as a guide for the delineation of flaps and may serve to conduct studies evaluating dose-effects, geometric patterns of failure or functional outcomes after reconstructive surgery. Changes in postoperative CTV definitions might be needed to improve risk/benefit ratio in the future based on surgery-induced changes.

RILA blood biomarker as a predictor of radiation-induced sarcoma in a matched cohort study.

PURPOSE: Radiation-induced sarcoma (RIS) is a rare but serious event. Its occurrence has been discussed during the implementation of new radiation techniques and justified appropriate radioprotection requirements. New approaches targeting intrinsic radio-sensitivity have been described, such as radiation-induced CD8 T-lymphocyte apoptosis (RILA) able to predict late radio-induced toxicities. We studied the role of RILA as a predisposing factor for RIS as a late adverse event following radiation therapy (RT). PATIENTS AND METHODS: In this prospective biological study, a total of 120 patients diagnosed with RIS were matched with 240 control patients with cancer other than sarcoma, for age, sex, primary tumor location and delay after radiation. RILA was prospectively assessed from blood samples using flow cytometry. RESULTS: Three hundred and forty-seven patients were analyzed (118 RIS patients and 229 matched control patients). A majority (74%) were initially treated by RT for breast cancer. The mean RT dose was comparable with a similar mean (± standard deviation) for RIS (53.7 ±â€¯16.0 Gy) and control patients (57.1 ±â€¯15.1 Gy) (p = .053). Median RILA values were significantly lower in RIS than in control patients with respectively 18.5% [5.5-55.7] and 22.3% [3.8-52.2] (p = .0008). Thus, patients with a RILA >21.3% are less likely to develop RIS (p < .0001, OR: 0.358, 95%CI [0.221-0.599]. CONCLUSION: RILA is a promising indicator to predict an individual risk of developing RIS. Our results should be followed up and compared with molecular and genomic testing in order to better identify patients at risk. A dedicated strategy could be developed to define and inform high-risk patients who require a specific approach for primary tumor treatment and long term follow-up.

Li+ solvation and kinetics of Li+-BF4-/PF6- ion pairs in ethylene carbonate. A molecular dynamics study with classical rate theories.

Using our polarizable force-field models and employing classical rate theories of chemical reactions, we examine the ethylene carbonate (EC) exchange process between the first and second solvation shells around Li+ and the dissociation kinetics of ion pairs Li+-[BF4] and Li+-[PF6] in this solvent. We calculate the exchange rates using transition state theory and correct them with transmission coefficients computed by the reactive flux, Impey, Madden, and McDonald approaches, and Grote-Hynes theory. We found that the residence times of EC around Li+ ions varied from 60 to 450 ps, depending on the correction method used. We found that the relaxation times changed significantly from Li+-[BF4] to Li+-[PF6] ion pairs in EC. Our results also show that, in addition to affecting the free energy of dissociation in EC, the anion type also significantly influences the dissociation kinetics of ion pairing.

[Preliminary results of whole breast helical tomotherapy with simultaneous integrated boost in the adjuvant treatment of breast cancer]. / Résultats préliminaires d'une tomothérapie hélicoïdale adjuvante avec boost intégré dans le cadre d'un traitement conservateur d'un cancer du sein.

PURPOSE: To evaluate the dosimetry and acute toxicity of helical tomotherapy for locoregional irradiation of patients after breast-conserving surgery. PATIENTS AND METHODS: Twenty breast cancer patients with breast-conserving surgery treated by helical tomotherapy have been studied. The median age was 49 (min: 25, max: 69). The whole breast, tumour bed and lymph nodes were prescribed 52.2 Gy, 63.8 Gy and 50.4 Gy, all in 29 fractions. The dose per fraction was 2.2 Gy to the boost, 1.8 Gy to the breast and 1.74 Gy to the lymph node volumes. The reproducibility was analysed by recording the daily shifts in x, y and z directions and roll rotation. All toxicities were described using the Common Terminology Criteria for Adverse Effects v3.0. RESULTS: Twenty-two tumours were irradiated. Six-eight percent were located in the inner quadrant. In 90 % of patients supraclavicular and internal mammary nodes were treated. The coverage of planning target volumes (PTV) was as follows: PTV boost: V107 = 0.3 % ± 0.5 SD, V95 = 98.4 % ± 1.9 SD; PTV breast: -V107 = 7.8 % ± 17.3 SD, V95 = 96.8 % ± 2.2 SD; PTV LN: V107 = 2.5 % ± 4.2 SD, V95 = 92.7 % ± 13.2 SD. The mean V20 of the homolateral lung was 18.9 % ± 3.5 SD. For left side lesion, the mean V30 of the heart was 0.9 % ± 0.8 SD. The mean V5 was: V5 homolateral lung: 73.1 % ± 11.8 ET, controlateral lung: 38.9 % ± 21, heart (left side breast): 57.3 % ± 21, controlateral breast: 15.5 % ± 9.6. Median shifts were as follow: x-axis -0.04 mm (IC 95: -0.4 +0.38), y-axis -0.37 mm ± 5.51 (IC 95: -0.88 +0.14), z-axis 2.90 mm ± 5.42 (IC 95:+2.4+3.4) and roll rotation 0.22 ± 1.10 (IC 95: -0.1+0.32). The treatment tolerance was acceptable with 1 definitive interruption couple of fractions before the end and 3 temporal interruptions for skin toxicity. No grade 3 or 4 toxicity. Ninety-five percent of patients experienced skin toxicity: 45 % grade 2. There were 3 cases of oesophagitis. The median follow-up of presented series is 9.7 months and all of the patients are free of disease without any residual early or late toxicity. CONCLUSIONS: Helical tomotherapy can achieve full target coverage while protected to the heart and ipsilateral lung. This treatment was well tolerated and reproducible. However, the low doses to normal tissue volumes need to be reduced in future studies.