Assessment of endpoint definitions in curative-intent trials for mucosal head and neck squamous cell carcinomas: Head and Neck Cancer International Group consensus recommendations.

Robust time-to-event endpoint definitions are crucial for the assessment of treatment effect and the clinical value of trial interventions. Here, the Head and Neck Cancer International Group investigated endpoint use in phase 3 trials and trials considered potentially practice-changing published between 2008 and 2021 in the curative-intent setting for patients with mucosal head and neck squamous cell carcinoma. Of the 92 trials reviewed, we show that all core components of endpoint reporting were heterogeneous, including definitions of common terms, such as overall survival and progression-free survival. Our report highlights the urgent need for harmonisation of fundamental components of clinical trial endpoints and the engagement of all stakeholders to ensure the transparent reporting of endpoint details.

Advances and residual knowledge gaps in the neck management of head and neck squamous cell carcinoma patients with advanced nodal disease undergoing definitive (chemo)radiotherapy for their primary.

PURPOSE: Substantial changes have been made in the neck management of patients with head and neck squamous cell carcinomas (HNSCC) in the past century. These have been fostered by changes in cancer epidemiology and technological progress in imaging, surgery, or radiotherapy, as well as disruptive concepts in oncology. We aimed to review changes in nodal management, with a focus on HNSCC patients with nodal involvement (cN+) undergoing (chemo)radiotherapy. METHODS: A narrative review was conducted to review current advances and address knowledge gaps in the multidisciplinary management of the cN+ neck in the context of (chemo)radiotherapy. RESULTS: Metastatic neck nodes are associated with poorer prognosis and poorer response to radiotherapy, and have therefore been systematically treated by surgery. Radical neck dissection (ND) has gradually evolved toward more personalized and less morbid approaches, i.e., from functional to selective ND. Omission of ND has been made feasible by use of positron-emission tomography/computed tomography to monitor the radiation response in cN+ patients. Human papillomavirus-driven oropharyngeal cancers and their cystic nodes have shown dramatically better prognosis than tobacco-related cancers, justifying a specific prognostic classification (AJCC) creation. Finally, considering the role of lymph nodes in anti-tumor immunity, de-escalation of ND and prophylactic nodal irradiation in combination are intense areas of investigation. However, the management of bulky cN3 disease remains an issue, as aggressive multidisciplinary strategies or innovative combined treatments have not yet significantly improved their prognosis. CONCLUSION: Personalized neck management is an increasingly important aspect of the overall therapeutic strategies in cN+ HNSCC.

ORGAVADS: establishment of tumor organoids from head and neck squamous cell carcinoma to assess their response to innovative therapies.

BACKGROUND: Radiotherapy is one of the cornerstones of the treatment of Head and Neck Squamous Cell Carcinomas (HNSCC). However, radioresistance is associated with a high risk of recurrence. To propose strategies (such as combinations with drugs) that could over intrinsic radioresistance, it is crucial to predict the response to treatment. Patient-Derived Tumor Organoids (PDTO) are in vitro tridimensional microtumors obtained from patient' own cancer samples. They have been shown to serve as reliable surrogates of the tumor response in patients. METHODS: The ORGAVADS study is a multicenter observational trial conducted to investigate the feasibility of generating and testing PDTO derived from HNSCC for the evaluation of sensitivity to treatments. PDTO are obtained after dissociation of resected tumors remaining from tissues necessary for the diagnosis. Embedding of tumor cells is then performed in extracellular matrix and culture in medium supplemented with growth factors and inhibitors. Histological and immunohistochemical characterizations are performed to validate the resemblance between PDTO and their original tumor. Response of PDTO to chemotherapy, radiotherapy and innovating combinations are assessed, as well as response to immunotherapy using co-cultures of PDTO with autologous immune cells collected from patient blood samples. Transcriptomic and genetic analyses of PDTO allow validation of the models compared to patients' own tumor and identification of potential predictive biomarkers. DISCUSSION: This study is designed to develop PDTO models from HNSCC. It will allow comparing the response of PDTO to treatment and the clinical response of the patients from whom they are derived. Our aim is to study the PDTO ability to predict the clinical response to treatment for each patient in view of a personalized medicine as well as to establish a collection of HNSCC models that will be useful for future innovative strategies evaluation. TRIAL REGISTRATION: NCT04261192, registered February 7, 2020, last amendment v4 accepted on June, 2021.

Visual outcomes of macular melanocytic lesions after early or delayed proton beam therapy.

PURPOSE: During their initial management, some macular melanocytic lesions can be closely monitored to wait for a documented growth before advocating a treatment by irradiation. However, the visual outcomes of this strategy have not yet been assessed. This study compares the visual outcomes of macular melanocytic lesions that underwent delayed proton beam therapy (PBT) after an initial observation to those treated early. METHODS: A total of 162 patients with suspicious melanocytic lesions whose margins were located within 3 mm of the fovea were recruited from two French ocular oncology centers. RESULTS: Overall, 82 patients treated with PBT within 4 months after the initial visit (early PBT group) were compared to 24 patients treated with delayed PBT (delayed PBT group) and 56 patients not treated with PBT (observation group). Visual acuity was not significantly different between baseline and last visit in the observation group (p = 0.325). Between baseline and last visit, the median [IQR] loss in visual acuity was significant in both the early (0.7 [0.2; 1.8], p < 0.001) and the delayed (0.5 [0.2; 1.5], p < 0.001) PBT groups. After irradiation, there was no significant difference between the early and delayed PBT groups for visual loss (p = 0.575), diameter reduction (p = 0.190), and thickness lowering (p = 0.892). In multivariate analysis, history of diabetes mellitus and Bruch's membrane rupture remained significantly associated with greater visual loss (p = 0.036 and p = 0.002, respectively). CONCLUSION: For small lesions in which there is no clear diagnosis of malignant melanoma, an initial close monitoring to document tumor growth does not impact visual prognosis, despite the potential complications associated with the untreated tumor. However, the survival should remain the main outcome of the treatment of these lesions.

Impact of lymphopenia on efficacy of nivolumab in head and neck cancer patients.

INTRODUCTION: Lymphopenia has been correlated with poorer survival in patients with metastatic cancers treated with anti-PD-1 immunotherapy. Treatments such as chemotherapy, surgery or radiotherapy can induce lymphopenia. Radiation-induced lymphopenia is common and prolonged in head and neck cancer (HNSCC) patients. We evaluated the impact of lymphopenia, on efficacy of anti PD-1 nivolumab immunotherapy in HNSCC patients. METHODS: a multicenter retrospective study included consecutive patients treated with nivolumab for recurrent/metastatic (R/M) HNSCC between January 2017 and June 2019. Lymphopenia was defined as lymphocyte counts below 1000 cells/mm3 upon initiation of nivolumab. Logistical regression was performed on factors associated with lymphopenia and ROC analyses assessed association between lymphopenia and survival. RESULTS: median age was 65. Of the 100 included patients, 60% had been treated by surgery, 67% had had first-line chemotherapy, and 89% loco-regional radiotherapy, 65% had concurrent chemotherapy with radiotherapy. Lymphopenia occurred in 56 (56%) patients upon initiation of nivolumab, with 29 (29%) patients having radiation-related lymphopenia. Prior locoregional radiotherapy was the only factor associated with lymphopenia upon initiation of nivolumab by logistical regression (OR 0.144 [0.029-0.706], p - 0.017). Lymphopenia upon initiation of nivolumab did not affect progression-free survival (PFS) (p - 0.815), overall survival (OS) (p - 0.783) or disease control rate (DCR) (p - 0.125). Locoregional symptomatology (HR - 2.37 [1.24-4.54], p - 0.009), metastatic symptomatology (HR - 4.74 [2.21-10.15], and persistent lymphopenia under nivolumab (HR 3.96 [1.19-13.17] p - 0.034) were associated with poorer OS in multivariate analysis. CONCLUSIONS: Lymphopenia upon initiation of nivolumab was not associated with poorer survival in R/M HNSCC patients, but persistence of lymphopenia during immunotherapy might be a prognostic marker of patient survival.

Impact of HPV status in T1-2 oropharyngeal squamous cell carcinoma with bulky N3 nodes: a multicenter GETTEC study.

PURPOSE: The purpose of our study was to investigate the impact of HPV status in oncologic outcomes in patients with T1-2 oropharyngeal SCC associated with bulky N3 nodes, and to determine progression prognosis factors aiming to define the best therapeutic strategies for these patients. METHODS: This multicenter retrospective study included patients with T1-2 oropharyngeal SCC with N3 nodes treated between 2010 and 2015 in 8 French comprehensive cancer centers. HPV status was determined with P16 hyperexpression in immunohistochemistry. HPV-positive patients were separated into 2 groups according to the associated smoking history (HPV + T +) or not (HPV + T-). We compared the oncological outcomes of patients according to HPV-status and smoking history. RESULTS: Of 67 patients with T1-2 N3 oropharyngeal SCC, 36 patients (53.7%) were HPV negative and 31 patients (46.3%) HPV positive. 2-year PFS was significantly better in HPV + T- group (p = 0.036). The risk of death or progression was significantly reduced in HPV + T- comparatively to HPV- (HR 0.25 95%CI [0.07; 0.89]). 2-year OS was significantly better in HPV + T- group than in the other two groups (p = 0.017). CONCLUSION: In patients with T1-2 oropharyngeal SCC associated with bulky N3 nodes, HPV positive patients without smoking history had better OS and PFS than HPV positive patients with smoking history and HPV negative patients. Thus, HPV status is a significant prognostic factor for survival but this benefit is altered when smoking history is associated. N3 HPV positive patients with smoking history have to be classified as high-risk.

International assessment of interobserver reproducibility of flap delineation in head and neck carcinoma.

Background: Several reports have suggested that radiotherapy after reconstructive surgery for head and neck cancer (HNC), could have deleterious effects on the flaps with respect to functional outcomes. To predict and prevent toxicities, flap delineation should be accurate and reproducible. The objective of the present study was to evaluate the interobserver variability of frequent types of flaps used in HNC, based on the recent GORTEC atlas.Materials and methods: Each member of an international working group (WG) consisting of 14 experts delineated the flaps on a CT set from six patients. Each patient had one of the five most commonly used flaps in HNC: a regional pedicled pectoralis major myocutaneous flap, a local pedicled rotational soft tissue facial artery musculo-mucosal (FAMM) (2 patients), a fasciocutaneous radial forearm free flap, a soft tissue anterolateral thigh (ALT) free flap, or a fibular free flap. The WG's contours were compared to a reference contour, validated by a surgeon and a radiologist specializing in HNC. Contours were considered as reproducible if the median Dice Similarity Coefficient (DSC) was > 0.7.Results: The median volumes of the six flaps delineated by the WG were close to the reference contour value, with approximately 50 cc for the pectoral, fibula, and ALT flaps, 20 cc for the radial forearm, and up to 10 cc for the FAMM. The volumetric ratio was thus close to the optimal value of 100% for all flaps. The median DSC obtained by the WG compared to the reference for the pectoralis flap, the FAMM, the radial forearm flap, ALT flap, and the fibular flap were 0.82, 0.40, 0.76, 0.81, and 0.76, respectively.Conclusions: This study showed that the delineation of four main flaps used for HNC was reproducible. The delineation of the FAMM, however, requires close cooperation between radiologist, surgeon and radiation oncologist because of the poor visibility of this flap on CT and its small size.

Dental management in head and neck cancers: from intensity-modulated radiotherapy with photons to proton therapy.

INTRODUCTION: Despite reduction of xerostomia with intensity-modulated compared to conformal X-ray radiotherapy, radiation-induced dental complications continue to occur. Proton therapy is promising in head and neck cancers to further reduce radiation-induced side-effects, but the optimal dental management has not been defined. MATERIAL AND METHODS: Dental management before proton therapy was assessed compared to intensity-modulated radiotherapy based on a bicentric experience, a literature review and illustrative cases. RESULTS: Preserved teeth frequently contain metallic dental restorations (amalgams, crowns, implants). Metals blur CT images, introducing errors in tumour and organ contour during radiotherapy planning. Due to their physical interactions with matter, protons are more sensitive than photons to tissue composition. The composition of restorative materials is rarely documented during radiotherapy planning, introducing dose errors. Manual artefact recontouring, metal artefact-reduction CT algorithms, dual or multi-energy CT and appropriate dose calculation algorithms insufficiently compensate for contour and dose errors during proton therapy. Physical uncertainties may be associated with lower tumour control probability and more side-effects after proton therapy. Metal-induced errors should be quantified and removal of metal restorations discussed on a case by case basis between dental care specialists, radiation oncologists and physicists. Metallic amalgams can be replaced with water-equivalent materials and crowns temporarily removed depending on rehabilitation potential, dental condition and cost. Implants might contraindicate proton therapy if they are in the proton beam path. CONCLUSION: Metallic restorations may more severely affect proton than photon radiotherapy quality. Personalized dental care prior to proton therapy requires multidisciplinary assessment of metal-induced errors before choice of conservation/removal of dental metals and optimal radiotherapy.

QUANTITATIVE ANALYSIS OF CHORIOCAPILLARIS ALTERATIONS IN SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY-ANGIOGRAPHY DURING RADIATION RETINOPATHY.

PURPOSE: To evaluate choriocapillaris alterations following proton beam therapy irradiation using swept-source optical coherence tomography-angiography, and to assess their correlation with the grade of radiation retinopathy (RR). METHODS: Eyes with uveal melanoma evaluated before and after irradiation with proton beam therapy were included, as well as the healthy fellow eye. The gradation of RR was based on a previously published classification. Choriocapillaris flow voids area was analyzed using Phansalkar thresholding. Retinal vascularization was described by foveal avascular zone (FAZ) perimeter, FAZ area, FAZ circularity index, and percentage of nonperfusion area (PAN) in the superficial capillary plexus (SCP) or deep capillary plexus. RESULTS: A total of 157 eyes of 83 patients were analyzed. Overall, there was a significant difference between the control group, the uveal melanoma before proton beam therapy group, and the grades of RR in the uveal melanoma after proton beam therapy group for FAZ perimeter ( P < 0.001), FAZ area ( P < 0.001), FAZ-circularity index ( P < 0.001), PAN-SCP ( P < 0.001), PAN-deep capillary plexus ( P < 0.001), and choriocapillaris flow voids area ( P < 0.001). Moreover, choriocapillaris flow voids area was significantly increased in the early stages of RR ( P = 0.003) and was further significantly correlated with FAZ perimeter ( P < 0.001), FAZ area ( P < 0.001), FAZ-circularity index ( P = 0.010), PAN-SCP ( P < 0.001), and PAN-deep capillary plexus ( P < 0.001). CONCLUSION: Quantitative optical coherence tomography-angiography alterations in the choriocapillaris microvascularization are an early biomarker of RR and are correlated to the severity of the disease.

Correction: Brochet et al. A Quantitative Comparison between Shannon and Tsallis-Havrda-Charvat Entropies Applied to Cancer Outcome Prediction. Entropy 2022, 24, 436.

Alexandre Huat, Sébastien Thureau, David Pasquier, Isabelle Gardin, Romain Modzelewski, David Gibon, Juliette Thariat and Vincent Grégoire were not included as authors in the original publication [...].

A Quantitative Comparison between Shannon and Tsallis-Havrda-Charvat Entropies Applied to Cancer Outcome Prediction.

In this paper, we propose to quantitatively compare loss functions based on parameterized Tsallis-Havrda-Charvat entropy and classical Shannon entropy for the training of a deep network in the case of small datasets which are usually encountered in medical applications. Shannon cross-entropy is widely used as a loss function for most neural networks applied to the segmentation, classification and detection of images. Shannon entropy is a particular case of Tsallis-Havrda-Charvat entropy. In this work, we compare these two entropies through a medical application for predicting recurrence in patients with head-neck and lung cancers after treatment. Based on both CT images and patient information, a multitask deep neural network is proposed to perform a recurrence prediction task using cross-entropy as a loss function and an image reconstruction task. Tsallis-Havrda-Charvat cross-entropy is a parameterized cross-entropy with the parameter α. Shannon entropy is a particular case of Tsallis-Havrda-Charvat entropy for α=1. The influence of this parameter on the final prediction results is studied. In this paper, the experiments are conducted on two datasets including in total 580 patients, of whom 434 suffered from head-neck cancers and 146 from lung cancers. The results show that Tsallis-Havrda-Charvat entropy can achieve better performance in terms of prediction accuracy with some values of α.

Avoidance or adaptation of radiotherapy in patients with cancer with Li-Fraumeni and heritable TP53-related cancer syndromes.

The management of patients with cancer and Li-Fraumeni or heritable TP53-related cancer syndromes is complex because of their increased risk of developing second malignant neoplasms after genotoxic stresses such as systemic treatments or radiotherapy (radiosusceptibility). Clinical decision making also integrates the risks of normal tissue toxicity and sequelae (radiosensitivity) and tumour response to radiotherapy (radioresistance and radiocurability). Radiotherapy should be avoided in patients with cancer and Li-Fraumeni or heritable TP53 cancer-related syndromes, but overall prognosis might be poor without radiotherapy: radioresistance in these patients seems similar to or worse than that of the general population. Radiosensitivity in germline TP53 variant carriers seems similar to that in the general population. The risk of second malignant neoplasms according to germline TP53 variant and the patient's overall oncological prognosis should be assessed during specialised multidisciplinary staff meetings. Radiotherapy should be avoided whenever other similarly curative treatment options are available. In other cases, it should be adapted to minimise the risk of second malignant neoplasms in patients who still require radiotherapy despite its genotoxicity, in view of its potential benefit. Adaptations might be achieved through the reduction of irradiated volumes using proton therapy, non-ionising diagnostic procedures, image guidance, and minimal stray radiation. Non-ionising imaging should become more systematic. Radiotherapy approaches that might result in a lower probability of misrepaired DNA damage (eg, particle therapy biology and tumour targeting) are an area of investigation.

Dose-Response and Normal Tissue Complication Probabilities after Proton Therapy for Choroidal Melanoma.

PURPOSE: Normal tissue complication probability (NTCP) models could aid the understanding of dose dependence of radiation-induced toxicities after eye-preserving radiotherapy of choroidal melanomas. We performed NTCP-modeling and established dose-response relationships for visual acuity (VA) deterioration and common late complications after treatments with proton therapy (PT). DESIGN: Retrospective study from single, large referral center. PARTICIPANTS: We considered patients from Nice, France, diagnosed with choroidal melanoma and treated primarily with hypofractionated PT (52 Gy physical dose in 4 fractions). Complete VA deterioration information was available for 1020 patients, and complete information on late complications was available for 991 patients. METHODS: Treatment details, dose-volume histograms (DVHs) for relevant anatomic structures, and patient and tumor characteristics were available from a dedicated ocular database. Least absolute shrinkage and selection operator (LASSO) variable selection was used to identify variables with the strongest impact on each end point, followed by multivariate Cox regressions and logistic regressions to analyze the relationships among dose, clinical characteristics, and clinical outcomes. MAIN OUTCOME MEASURES: Dose-response relationship for VA deterioration and late complications. RESULTS: Dose metrics for several structures (i.e., optic disc, macula, retina, globe, lens, ciliary body) correlated with clinical outcome. The near-maximum dose to the macula showed the strongest correlation with VA deterioration. The near-maximum dose to the retina was the only variable with clear impact on the risk of maculopathy, the dose to 20% of the optic disc had the largest impact on optic neuropathy, dose to 20% of cornea had the largest impact on neovascular glaucoma, and dose to 20% of the ciliary body had the largest impact on ocular hypertension. The volume of the ciliary body receiving 26 Gy was the only variable associated with the risk of cataract, and the volume of retina receiving 52 Gy was associated with the risk of retinal detachment. Optic disc-to-tumor distance was the only variable associated with dry eye syndrome in the absence of DVH for the lachrymal gland. CONCLUSIONS: VA deterioration and specific late complications demonstrated dependence on dose delivered to normal structures in the eye after PT for choroidal melanoma. VA deterioration depended on dose to a range of structures, whereas more specific complications were related to dose metrics for specific structures.

Salivary gland carcinoma in children and adolescents: The EXPeRT/PARTNER diagnosis and treatment recommendations.

Salivary gland carcinomas (SGCs) are rare during childhood and adolescence. Consequently, no standardized recommendations for the diagnosis and therapeutic management of pediatric SGC are available, and pediatric oncologists and surgeons generally follow adult guidelines. Complete surgical resection with adequate margins constitutes the cornerstone of treatment. However, the indications and modalities of adjuvant therapy remain controversial and may be challenging in view of the potential long-term toxicities in the pediatric population. This paper presents the consensus recommendations for the diagnosis and treatment of children and adolescents with SGCs, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded PARTNER project (Paediatric Rare Tumours Network - European Registry).

Immunotherapy and Radiotherapy for Older Cancer Patients during the COVID-19 Era: Proposed Paradigm by the International Geriatric Radiotherapy Group.

BACKGROUND: Older cancer patients with locally advanced or metastatic disease may benefit from chemotherapy alone or combined with radiotherapy. However, chemotherapy is often omitted either because of physician bias or because of its underlying comorbidity, thus compromising their survival. The coronavirus disease 19 (COVID-19) pandemic is compounding this issue because of the fear of immunosuppression induced by chemotherapy on the elderly which makes them more vulnerable to the virus. SUMMARY: Immunotherapy has less effect on the patient bone marrow compared to chemotherapy. The potential synergy between radiotherapy and immunotherapy may improve local control and survival for older patients with selected cancer. Preliminary data are encouraging because of better survival and local control in diseases which are traditionally resistant to radiotherapy and chemotherapy such as melanoma and renal cell carcinoma. Key Message: We propose a new paradigm combining immunotherapy at a reduced dose and/or extended dosing intervals and hypofractionated radiotherapy for older patients with selected cancer which needs to be tested in future clinical trials.

COMPARATIVE EFFECTIVENESS OF PROTON BEAM VERSUS PHOTODYNAMIC THERAPY TO SPARE THE VISION IN CIRCUMSCRIBED CHOROIDAL HEMANGIOMA.

PURPOSE: The aim of this study was to compare the functional and anatomical effectiveness of photodynamic therapy (PDT) versus proton beam therapy (PBT) in a real-life setting for the treatment of circumscribed choroidal hemangioma. METHODS: A total of 191 patients with a diagnosis of circumscribed choroidal hemangioma and treated by PBT or PDT were included for analyses. RESULTS: The 119 patients (62.3%) treated by PDT were compared with the 72 patients treated by PBT. The final best-corrected visual acuity did not differ significantly between the two groups (P = 0.932) and final thickness was lower in the PBT compared with the PDT group (P = 0.001). None of the patients treated by PBT needed second-line therapy. In comparison, 53 patients (44.5%) initially treated by PDT required at least one other therapy and were associated with worse final best-corrected visual acuity (P = 0.037). In multivariate analysis, only an initial thickness greater than 3 mm remained significant (P = 0.01) to predict PDT failure with an estimated odds ratio of 2.72, 95% confidence interval (1.25-5.89). CONCLUSION: Photodynamic therapy and PBT provide similar anatomical and functional outcomes for circumscribed choroidal hemangioma ≤3 mm, although multiple sessions are sometimes required for PDT. For tumors >3 mm, PBT seems preferable because it can treat the tumor in only 1 session with better functional and anatomical outcomes.

Tumour control probability after Ruthenium-106 brachytherapy for choroidal melanomas.

Purpose: Ruthenium-106 (Ru-106) brachytherapy is a common eye-preserving treatment for choroidal melanomas. However, a dose-response model describing the relationship between the actual delivered tumour dose and tumour control has, to the best of our knowledge, not previously been quantified for Ru-106 brachytherapy; we aimed to rectify this.Material and methods: We considered consecutive patients with primary choroidal melanomas, treated with Ru-106 brachytherapy (2005-2014). Dosimetric plans were retrospectively recreated using 3D image-guided planning software. Pre-treatment fundus photographies were used to contour the tumour; post-treatment photographies to determine the accurate plaque position. Patient and tumour characteristics, treatment details, dose volume histograms, and clinical outcomes were extracted. Median follow-up was 5.0 years. The relationship between tumour dose and risk of local recurrence was examined using multivariate Cox regression modelling, with minimum physical tumour dose (D99%) as primary dose metric.Results: We included 227 patients with median tumour height and largest base dimension of 4 mm (range 1-12, IQR 3-6) and 11 mm (range 4-23, IQR 9-13). The estimated 3 year local control was 82% (95% CI 77-88). Median D99% was 105 Gy (range 6-783, IQR 65-138); this was the most significant factor associated with recurrence (p < .0001), although tumour height, combined TTT and Ru-106 brachytherapy, and sex were also significant. The hazard ratio (HR) for a 10 Gy increase in D99% was 0.87 (95% CI 0.82-0.93). Using biological effective dose in the model resulted in no substantial difference in dose dependence estimates. Robustness cheques with D1-99% showed D99% to be the most significant dose metric for local recurrence.Conclusion: The minimum tumour dose correlated strongly with risk of tumour recurrence, with 100 Gy needed to ensure at least 84% local control at 3 years.

RGD-functionalized magnetosomes are efficient tumor radioenhancers for X-rays and protons.

Although chemically synthesized ferro/ferrimagnetic nanoparticles have attracted great attention in cancer theranostics, they lack radio-enhancement efficacy due to low targeting and internalization ability. Herein, we investigated the potential of RGD-tagged magnetosomes, bacterial biogenic magnetic nanoparticles naturally coated with a biological membrane and genetically engineered to express an RGD peptide, as tumor radioenhancers for conventional radiotherapy and proton therapy. Although native and RGD-magnetosomes similarly enhanced radiation-induced damage to plasmid DNA, RGD-magnetoprobes were able to boost the efficacy of radiotherapy to a much larger extent than native magnetosomes both on cancer cells and in tumors. Combined to magnetosomes@RGD, proton therapy exceeded the efficacy of X-rays at equivalent doses. Also, increased secondary emissions were measured after irradiation of magnetosomes with protons versus photons. Our results indicate the therapeutic advantage of using functionalized magnetoparticles to sensitize tumors to both X-rays and protons and strengthen the case for developing biogenic magnetoparticles for multimodal nanomedicine in cancer therapy.

Locoregional control, progression-free survival and morbidity rates in N3 head and neck cancer patients with low primary tumour burden: A 301-patient study.

OBJECTIVES: In patients with N3 head and neck squamous cell carcinoma (HNSCC), N3 disease is associated with high regional relapse and metastatic risks. Patients with resectable N3 disease have better prognosis although their metastatic risk may be similar as in patients with unresectable disease. Neoadjuvant chemotherapy has been associated with lower metastatic rates, but N3 patients may die of rapid locoregional progression. We assessed outcomes with the three modalities in patients with low primary burden to better assess the specific prognosis of N3 disease. METHODS: This retrospective multicentric study included T0-2 N3 HNSCC patients. Outcomes and morbidity in upfront neck dissection (uND) vs non-surgical groups were analysed and oncological outcomes and morbidity compared between patients undergoing chemoradiation or neoadjuvant chemotherapy in patients with initially unresectable N3 nodes. RESULTS: Of 301 patients, 142 (47%) underwent uND, 68 (23%) neoadjuvant chemotherapy and 91 (30%) chemoradiation. The 24- and 60-month incidence of locoregional relapse was 23.2% [18.3%; 28.4%] and 27.4% [21.8%; 33.3%]; it was lower in patients undergoing uND (P = .006). In patients with non-surgical treatments, success rates were 57.8% [49.4%; 66.3%] after chemoradiation and 38.1% [29.6%; 46.7%] after neoadjuvant chemotherapy (P = .001). Overall morbidity was more frequent in patients undergoing uND (68.8%) (P < .001). CONCLUSION: uND improved locoregional control but increased morbidity and showed no survival benefit. Success rates were better after chemoradiation versus neoadjuvant chemotherapy. Neoadjuvant chemotherapy did not reduce metastatic rates but non-responders to chemoradiation had poor PFS and survival rate, suggesting that predictive criteria are warranted.

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.

BACKGROUND: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. METHODS: Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FINDINGS: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. INTERPRETATION: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FUNDING: Nanobiotix SA.