Prospective comparison of acute severe toxicities between smokers and non-smokers during radiotherapy for head and neck cancers.

BACKGROUND AND PURPOSE: The association between smoking and acute radiation toxicities of head and neck cancer (HNC) is currently unproven. The aim of the study was to compare the occurrence of acute severe toxicity between active and non-active smokers treated for HNC by radiotherapy. MATERIALS AND METHODS: A prospective monocentric cohort study included patients treated by (chemo)radiotherapy for HNC from January 2021 to January 2023. Smoking status was recorded. Patients underwent a medical exam weekly during the radiotherapy to report acute toxicities according to the Common Terminology Criteria for Adverse Effects system version 5.0. Primary endpoint was the occurrence of at least one grade ≥ 3 acute toxicity among mucositis, dysphagia and dermatitis. RESULTS: Among the 102 patients included, 27.4 % were active smokers, 58.8 % were former smokers and 13.7 % had never smoked. Regarding toxicity, 23.5 % (n = 24) patients experienced severe mucositis, 37.2 % (n = 38) severe dysphagia, 13.7 % (n = 14) severe dermatitis and 54.9 % (n = 56) experienced at least one of them. Occurrence of severe acute toxicity was not statistically associated with smoking during radiotherapy (64.3 % among active smokers versus 51.3 % among non-active smokers; p = 0.24). On multivariate analysis, concurrent chemotherapy (87.5 % vs 65.2 %; OR = 5.04 [1.64-15.52]; p = 0.004) and 2.12 Gy versus 2 Gy fractionation schedule (64.3 % vs 41.3 %; OR = 2.53 [1.09-5.90]; p = 0.03) were significantly associated with severe acute toxicity. CONCLUSION: This study did not find an association between smoking during radiotherapy for HNC and occurrence of severe acute toxicities.

[Limits of dose constraint definition for organs at risk specific to stereotactic radiotherapy]. / Limites de la définition des contraintes de dose pour les organes à risque spécifiques à la radiothérapie stéréotaxique.

Stereotactic radiotherapy is a very hypofractionated radiotherapy (>7.5Gy per fraction), and therefore is more likely to induce late toxicities than conventional normofractionated irradiations. The present study examines four frequent and potentially serious late toxicities: brain radionecrosis, radiation pneumonitis, radiation myelitis, and radiation-induced pelvic toxicities. The critical review focuses on the toxicity scales, the definition of the dose constrained volume, the dosimetric parameters, and the non-dosimetric risk factors. The most commonly used toxicity scales remain: RTOG/EORTC or common terminology criteria for adverse events (CTCAE). The definition of organ-at-risk volume requiring protection is often controversial, which limits the comparability of studies and the possibility of accurate dose constraints. Nevertheless, for the brain, whatever the indication (arteriovenous malformation, benign tumor, metastasis of solid tumors...), the association between the volume of brain receiving 12Gy (V12Gy) and the risk of cerebral radionecrosis is well established for both single and multi-fraction stereotactic irradiation. For the lung, the average dose received by both lungs and the V20 seem to correlate well with the risk of radiation-induced pneumonitis. For the spinal cord, the maximum dose is the most consensual parameter. Clinical trial protocols are useful for nonconsensual dose constraints. Non-dosimetric risk factors should be considered when validating the treatment plan.

[Radiotherapy and targeted therapy for the management of breast cancer: A review]. / Radiothérapie et thérapie ciblée pour la prise en charge du cancer du sein : mise au point.

The purpose of this study was to review the current knowledge regarding combinations of the most commonly used targeted therapies or those under development for the management of breast cancer with radiation therapy. Several studies have shown that the combination of radiation therapy and tamoxifen increased the risk of radiation-induced lung toxicity; therefore, the two modalities are generally not given concurrently. The combination of HER2 inhibitors (trastuzumab, pertuzumab) and radiation therapy appeared to be safe. However, trastuzumab emtansine (T-DM1) should not be given concomitantly with brain radiation therapy because this combination may increase the risk of brain radionecrosis. The combination of radiation therapy with other new targeted therapies such as new selective estrogen receptor modulators (SERDs), lapatinib, cell cycle inhibitors, immune checkpoint inhibitors, or molecules acting on DNA damage repair seems feasible but has been mainly evaluated on retrospective or prospective studies with small numbers of patients. Moreover, there is a great heterogeneity between these studies regarding the dose and fractionation used in radiotherapy, the dosage of systemic treatments and the sequence of treatments used. Therefore, the combination of these new molecules with radiotherapy should be proposed sparingly, under close monitoring, pending the ongoing prospective studies cited in this review.

[Biological, preclinical and clinical aspects of the association between radiation therapy and CDK4/6 inhibitors]. / Aspects biologiques, précliniques et cliniques de l'association de radiothérapie et d'inhibiteur de CDK 4/6.

Several clinical studies have shown that CDK4/6 inhibitors (CDK4/6i) improve survival in patients with metastatic or locally advanced HR-positive, HER-2-negative breast cancer (BC). The aim of this review was to synthesize the biological, preclinical and clinical aspects of the treatment of BC with CDK4/6i, with a focus on the combination of CDK4/6i and radiotherapy. The DNA damage induced after exposure of cells to ionizing radiation activates control pathways that inhibit cell progression in the G1 and G2 phases and induce a transient delay in progression in the S phase. These checkpoints are in particular mediated by cyclin-dependent kinases (CDK) 4/6 activated by cyclin D1. Several preclinical studies have shown that CDK4/6i could be used as radiosensitizers in non-small cell lung cancer, medulloblastoma, brainstem glioma and breast cancer. CDK4/6 inhibition also protected against radiation-induced intestinal toxicities by inducing redistribution of quiescent intestinal progenitor cells, making them less radiosensitive. Clinical data on the combination of CDK inhibitors and radiotherapy for both locoregional and metastatic irradiation are based on retrospective data. Nevertheless, the most optimal therapeutic sequence would be radiotherapy followed by palbociclib. Pending prospective clinical trials, the concomitant combination of the two treatments should be done under close supervision.

Multidisciplinary management and role of reirradiation in the treatment of a breast cancer patient with four locoregional recurrences.

Breast cancer is a frequent and sometimes fatal disease. The risk of locoregional recurrence has considerably decreased since the introduction of adjuvant treatments (radiotherapy, chemotherapy, hormone therapy). Nevertheless, some patients present a risk of multiple local recurrences. We report here the case of a patient who had four locoregional breast cancer recurrences. There is currently no validated biomarker that allows the prediction of recurrence. Salvage surgery, most often mastectomy, remains the recommended treatment for the management of these recurrences in the irradiated field. However, increasingly, depending on the patient's wishes and the technical possibilities of multiple surgeries, the question of a second conservative treatment and reirradiation arises. This type of management must in all cases be multidisciplinary and in specialized centers. Reirradiation must in any case try to give maximum priority to the protection of healthy tissue already irradiated.

AFSOS-SFRO-SFH-SFNEP-SFCE-GFRP guidelines on radio-induced nausea and vomiting.

INTRODUCTION: The prevalence of radiation-induced nausea and vomiting varies between 40% and 80%. They have many consequences on treatment and comorbidities. This work thus aimed to define clinical practice guidelines for the management of radiation-induced nausea and vomiting. METHODS: XXXXX, XXXX, XXX, XXXXX, XXXX and XXXX compiled a working group who draft these recommendations. RESULTS: The assessment of the emetogenic risk found two main predictive factors: 1) the irradiated anatomical location, 2) an associated concomitant chemotherapy. In the case of exclusive radiotherapy, primary antiemetic prophylaxis depends on the emetogenic risk (the irradiated anatomical location). In the case of concomitant chemotherapy, the emetogenic risk is generally higher and the primary antiemetic prophylaxis corresponds to that of chemotherapy-induced nausea and vomiting. In cases where symptoms persist, remedial treatments are poorly codified. CONCLUSION: Radiation-induced nausea and vomiting remains underdiagnosed and undertreated, its rapid detection and treatment are essential to reinstate good clinical practice.

Can we treat with radiation breast cancer patients with covid-19 infection? Results from a prospective study.

PURPOSE: The coronavirus disease 2019 (covid-19) caused by the severe acute respiratory syndrome coronavirus 2 (Sars-Cov-2) is at the origin of a global pandemic. This pandemic has prompted the current health system to reorganize and rethink the care offered by health establishments. We report the early and late toxicity in patients infected with covid-19 treated at the same time for early-stage breast cancer. MATERIAL AND METHODS: This is a monocentric prospective study of patients treated in our hospital between March and June 2020 who were diagnosed with covid-19 infection. The inclusion criteria were to be irradiated for early-stage breast cancer and to have a positive covid diagnosis on a polymerase chain reaction (PCR) test and/or a lung computed tomography (CT) scan and/or suggestive clinical symptoms. All of them needed 6 months follow-up clinic after the end of the radiotherapy with clinical examination, mammogram, as well as CT scan to evaluate the lung status. Radiotherapy consisted of breast or chest wall irradiation with or without lymph node irradiation, with protocols adapted to pandemic situation. The treatment-related toxicity was graded according to the Common Toxicology Criteria for Adverse Events (version 4.03). RESULTS: All 350 patients treated for early-stage breast cancer were studied. Of them, 16 presented clinical symptoms of covid-19 infection, and of them 12 had clinical, CT scan and PCR confirmation. This entire cohort of 12 patients with median age of 56years (range: 42-72 years) underwent their radiotherapy. During the radiotherapy, nine patients presented radiodermatitis: eight grade 1 (66%) and one grade 2 (8%). Two patients with lymph nodes irradiation presented grade 2 oesophagitis. Late toxicity was evaluated 6 months after the end of the radiotherapy, and there was no radiation or covid lung sequel on the CT scans. One patient presented covid-related dyspnoea, and two had fibrosis. CONCLUSION: The half-year follow-up of prospective covid-19 cohort, treated for early-stage breast cancer demonstrated an acceptable toxicity profile with few low-grade adverse events. It seems that the covid-19 infection does not appear to increase the side effects of radiotherapy. Therefore radiotherapy should not be delayed.

Unusual severe radiation-induced toxicity in a patient with discoid lupus erythematosus: A case report and critical review of the literature.

Data on the incidence and severity of radiation-induced toxicity in patients with systemic and/or cutaneous lupus erythematosus (SLE/CLE) are very limited. After reporting the case of a patient who experienced major toxicity and CLE flare in the irradiated area following breast irradiation, we conducted a comprehensive literature review of available data in this setting. The few retrospectives studies which have evaluated both the risk of toxicity in SLE/CLE patients and/or the potential induction or reactivation of SLE/CLE with radiotherapy have not shown differences between SLE/CLE patients and controls. Several other factors such as concurrent chemotherapy, a particular genetic background, or lupus treatments (essentially hydroxychloroquine) can explain severe radiation-induced toxicity. Therefore, patients with SLE/CLE should be irradiated like patients without SLE/CLE, with close monitoring during radiotherapy if other risk factors exist. Further studies examining a larger number of patients would probably allow a better understanding of the radiosensitivity of these patients.

Is cancer a prognostic factor for severe COVID-19, especially for breast cancer patients?

The coronavirus disease 2019 (COVID-19) pandemic has caused a global upheaval in our health care system. Our hospital facilities have been subjected to a major influx of patients and the prevention of cross-contamination has been a key issue in the spread of the virus. New recommendations for good hygiene practice and new recommendations for disease management have emerged to limit the spread of the virus and reorganize the provision of care in key services. Many studies have attempted to identify factors that contribute to poor prognosis for COVID-19 infection. Among them, cancer patients, were considered more at risk of developing severe forms of COVID-19. In this article, we provide an overview of the current state of the pandemic as well as new recommendations for disease management that have emerged in oncology and radiation therapy in particular. In this article, we will try to provide some answers through a review of the literature to the question: is cancer a prognostic factor for severe COVID-19?

Clinical practice of breast cancer protontherapy: A single-centre experience from selection to treatment.

PURPOSE: Breast protontherapy efficiently limits cardiac, lung and contralateral breast exposure, which may clinically translate into better late tolerance profile compared with classic photon techniques. While breast protontherapy is already implemented in the United States and in some European countries, clinical experience of breast cancer protontherapy is currently limited in France. The aim of this study is to evaluate the clinical practice of breast cancer protontherapy at the Institut Curie in order to implement this technique at a larger scale. MATERIALS AND METHODS: Data from all breast cancer patients that have been addressed to the protontherapy centre of Orsay (CPO, Institut Curie) for adjuvant breast protontherapy were retrieved. We analysed why these patients were ultimately treated with protontherapy or not. RESULTS: Between November 2019 and November 2020, eleven breast cancer patients have been evaluated for adjuvant protontherapy at the CPO. Two of them were ultimately treated with proton beams; adjuvant breast protontherapy therapy was well tolerated. The nine other patients were not treated with protontherapy due to lack of availability of protontherapy treatment rooms in acceptable time limits, at the time of patient evaluation. CONCLUSION: Despite dosimetric advantages and excellent clinical tolerance, lack of availability of protontherapy machines currently limits wider implementation of breast protontherapy.

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.

Imaging issues specific to hadrontherapy (proton, carbon, helium therapy and other charged particles) for radiotherapy planning, setup, dose monitoring and tissue response assessment.

Imaging is critical to each step of precision radiation therapy, i.e. planning, setup, delivery and assessment of response. Hadrontherapy can be considered to deliver more precise dose distribution that may better spare normal tissues from intermediate low doses of radiation. In addition, hadrontherapy using high linear energy transfer ions may also be used for dose escalation on biological target volumes defined by functional imaging. However, the physical characteristics of hadrontherapy also make it more demanding in terms of imaging accuracy and image-based dose calculation. Some of the developments needed in imaging are specific to hadrontherapy. The current review addresses current status of imaging in proton therapy and the drawbacks of photon-based imaging for hadrons. It also addresses requirements in hadrontherapy planning with respect to multimodal imaging for proper target and organ at risk definition as well as to target putative radioresistant areas such as hypoxic ones, and with respect to dose calculation using dual energy CT, MR-proton therapy, proton radiography. Imaging modalities, such as those used in photon-based radiotherapy (intensity modulated and stereotactic radiotherapy), are somewhat already implemented or should be reaching "routine" hadrontherapy (at least proton therapy) practice in planning, repositioning and response evaluation optimizable within the next five years. Online monitoring imaging by PET, as currently developed for hadrontherapy, is already available. Its spatiotemporal limits restrict its use but similar to prompt gamma detection, represents an area of active research for the next 5 to 10 years. Because of the more demanding and specific dose deposit characteristics, developments image-guided hadrontherapy, such as specific proton imaging using tomography or ionoacoustics, as well as delivery with MR-proton therapy, may take another 10 years to reach the clinics in specific applications. Other aspects are briefly described such as range monitoring. Finally, the potential of imaging normal tissue changes and challenges to assess tumour response are discussed.

[Proton therapy for head and neck squamous cell carcinomas: From physics to clinic]. / Protonthérapie des carcinomes épidermoïdes des voies aérodigestives supérieures : de la physique à la clinique.

Intensity-modulated radiation therapy (IMRT) is presently the recommended technique for the treatment of locally advanced head and neck carcinomas. Proton therapy would allow to reduce the volume of irradiated normal tissue and, thus, to decrease the risk of late dysphagia, xerostomia, dysgeusia and hypothyroidism. An exhaustive research was performed with the search engine PubMed by focusing on the papers about the physical difficulties that slow down use of proton therapy for head and neck carcinomas. Range uncertainties in proton therapy (±3 %) paradoxically limit the use of the steep dose gradient in distality. Calibration uncertainties can be important in the treatment of head and neck cancer in the presence of materials of uncertain stoichiometric composition (such as with metal implants, dental filling, etc.) and complex heterogeneities. Dental management for example may be different with IMRT or proton therapy. Some uncertainties can be somewhat minimized at the time of optimization. Inter- and intrafractional variations and uncertainties in Hounsfield units/stopping power can be integrated in a robust optimization process. Additional changes in patient's anatomy (tumour shrinkage, changes in skin folds in the beam patch, large weight loss or gain) require rescanning. Dosimetric and small clinical studies comparing photon and proton therapy have well shown the interest of proton therapy for head and neck cancers. Intensity-modulated proton therapy is a promising treatment as it can reduce the substantial toxicity burden of patients with head and neck squamous cell carcinoma compared to IMRT. Robust optimization will allow to perform an optimal treatment and to use proton therapy in current clinical practice.

[Boost in proton for locally advanced nasopharyngeal carcinoma: A Curie Institute experience]. / Complément de dose de protons pour les cancers du nasopharynx localement évolués : une expérience de l'institut Curie.

PURPOSE: The aim of this study was to assess the treatment outcome and toxicity for patients with locally advanced nasopharyngeal carcinoma treated with a complementary dose with proton. PATIENTS AND METHODS: Between November 1999 and September 2016, 17 patients have been treated for a stage III-IVa nasopharyngeal carcinoma in the proton therapy centre of Curie Institute. Bilateral lymph node in the neck (I-V levels) received from 40 to 54Gy with photon beam. The primary tumor volume including microscopically extensions received a complementary dose with proton in order to reach the dose of 70 to 78Gy. All the patients received a concomitant chemotherapy. The end-points of the study were loco-regional control, survival, and treatment-related toxicity. RESULTS: Patients characteristics were: median age 49, 71 % male, 88% stage IVa, with a majority (82%) of T4N0M0. The median follow-up was 99 months. The 2-, 5- and 10-year actuarial locoregional free survival and overall survival were 94% and 88%, 86% and 74%, and 86% and 66%, respectively. The grade≥3 late adverse events were sphenoid bone radionecrosis (5.9%) and hearing loss (23.5%). CONCLUSION: This study showed that a complementary dose with proton seems to be a good option for the treatment of locally advanced nasopharyngeal carcinoma, particularly for T4N0M0.

[Image-guided radiotherapy for head and neck carcinoma]. / Radiothérapie guidée par l'image des cancers ORL.

Intensity-modulated radiotherapy, combined with chemotherapy, is the recommended treatment of locally advanced head and neck carcinoma, as a definitive treatment or as an adjuvant treatment following surgery. This technique offers the ability to sculpt the dose closely to the tumor volume. With this close conformity, it is essential to ensure that every day during the treatment the patient position and anatomy are similar to those at the time of treatment planning. Inevitably, there will be uncertainties introduced in this process and a planning target volume margins are added around the tumour volume to compensate for these uncertainties. Various imaging technologies have been integrated with linear accelerators to deal with patient position and potentially reduce the margins. This forms the foundations of image-guided radiotherapy. In patients with head and neck carcinoma systematic and random set-up uncertainties are frequent. The 3D volumetric image guidance systems are efficient to reduce these uncertainties. After a summary about the different sources of uncertainties, this review will present successively the different techniques of image-guided radiotherapy for head and neck carcinomas, along with their advantages and limitations. Then we will focus on the methods used to reduce the set-up uncertainties and finally discuss the concept of adaptive radiotherapy and its application in clinical practice.

[Small cell neuroendocrine carcinoma of the upper urinary tract: A case report]. / Carcinome neuroendocrine à petites cellules des voies urinaires excrétrices supérieures: à propos d'un cas.

Small cell neuroendocrine carcinoma of the upper urinary tract is extremely rare. To our knowledge, only 25 cases have been reported in the literature. The current study reports the case of an 80-year-old patient who suffered from macroscopic haematuria. A first screening by thoracic-abdominal-pelvic CT scan showed a mass located in the patient's left ureter and a left nephro-ureterectomy was consequently performed. The pathological examination of the resected specimen allowed the diagnosis of a small cell neuroendocrine carcinoma of the left ureter. After four months of follow-up, a PET-CT detected an isolated local recurrence on the left common iliac lymphadenopathy. After seven cycles of chemotherapy (carboplatin-etoposide), we observed a partial response followed by a new progression. It was then decided to perform an image-guided radiotherapy at a dose of 46.8 Gy, at 1.8 Gy per fraction, during 37 days to the left common iliac lymphadenopathy. After 16 months of follow-up, a complete metabolic remission was achieved. Indeed, this observation, followed by a short literature review, demonstrates the interest of radiotherapy for the treatment of a rare cancer: the small cell neuroendocrine carcinoma of the upper urinary tract.

[Ascaridiasis zoonoses: visceral larva migrans syndromes]. / Zoonoses d'origine ascaridienne: les syndromes de Larva migrans visceral.

The syndrome of Visceral Larva Migrans is a zoonotic disease due to the migration in human of nematodes larval, specially ascarid. Since the larvae fail to complete their migrating cycle in humans, the diagnosis of Toxocariasis infection remains only serologic. We have been able to demonstrate by the technique of agar diffusion and the Western-blotting method that the etiology due to Toxocara canis was twice as much frequent as the one due to Toxocara cati in the syndrome of Visceral and Ocular Larva Migrans. The use of numerous antigens from adult nematodes, mainly Ascaris suum, has shown, than in France, in the syndrome of VLM at least 12% of the cases were certainly due to other nematodes. Nippostrongylus brasiliensis (or another similar nematode) of the rat might be responsible. The existence of numerous clinical and biological cases found negative in serology, allow us to suggest that some other larval nematodes, may be from wild animals, might play an etiological role.