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Background: Despite early diagnosis, approximately 20% of patients with ER-positive and HER2-negative breast cancer (BC) will experience disease recurrence. Improved survival has been reported with adjuvant treatment combining cyclin-dependent kinase 4/6 inhibitors with endocrine therapy, in high-risk patients with ER-positive and HER2-negative BC, regardless of age. Older patients have higher rates of ER-positive/HER2-negative BC than younger patients. Methods: In this real-world data analysis, MonarchE and NataLEE high-risk patients accounted for 9.5% and 33% of patients undergoing upfront surgery, respectively. Significantly higher eligibility rates were observed in patients who underwent a mastectomy, >70 years and ≤40 years for adjuvant abemaciclib and ribociclib, and in patients >80 years for ribociclib. Results: Eligibility rates in patients ≤40 years and >80 years who underwent mastectomy were 27.8% and 24.7% for abemaciclib, respectively, and 56.6% and 65.2% for ribociclib, respectively. A higher discontinuation rate for abemaciclib was reported in patients aged ≥65 years and it can be assumed that discontinuation rates may increase in even older patients. Conclusions: If the results of the NataLEE trial translate into clinical practice, the number of patients potentially eligible for adjuvant CDK4/6 inhibitors may increase, especially in the elderly population.

Background: Whether re-excision (RE) of a soft tissue sarcoma (STS) of limb or trunk should be systematized as adjuvant care and if it would improve metastatic free survival (MFS) are still debated. The impact of resection margins after unplanned macroscopically complete excision (UE) performed out of a NETSARC reference center or after second resection was further investigated., Methods: This large nationwide series used data from patients having experienced UE outside of a reference center from 2010 to 2019, collected in a French nationwide exhaustive prospective cohort NETSARC. Patient characteristics and survival distributions in patients reexcised (RE) or not (No-RE) are reported. Multivariate Cox proportional hazard model was conducted to adjust for classical prognosis factors. Subgroup analysis were performed to identify which patients may benefit from RE., Results: Out of 2371 patients with UE for STS performed outside NETSARC reference centers, 1692 patients were not reviewed by multidisciplinary board before treatment decision and had a second operation documented. Among them, 913 patients experienced re-excision, and 779 were not re-excised. Characteristics were significantly different regarding patient age, tumor site, size, depth, grade and histotype in patients re-excised (RE) or not (No-RE). In univariate analysis, final R0 margins are associated with a better MFS, patients with R1 margins documented at first surgery had a better MFS as compared to patients with first R0 resection. The study identified RE as an independent favorable factor for MFS (HR 0.7, 95% CI 0.53-0.93; p = 0.013). All subgroups except older patients (>70 years) and patients with large tumors (>10 cm) had superior MFS with RE., Conclusions: RE might be considered in patients with STS of limb or trunk, with UE with macroscopic complete resection performed out of a reference center, and also in originally defined R0 margin resections, to improve LRFS and MFS. Systematic RE should not be advocated for patients older than 70 years, or with tumors greater than 10 cm.

Background: RT-induced hyalinization/fibrosis was recently evidenced as a significant independent predictor for complete response to neoadjuvant radiotherapy (RT) and survival in patients with soft tissue sarcoma (STS). Purpose: Non-invasive predictive markers of histologic response after neoadjuvant RT of STS are expected. Materials and Methods: From May 2010 to April 2017, patients with a diagnosis of STS who underwent neoadjuvant RT for limb STS were retrieved from a single center prospective clinical imaging database. Tumor Apparent Diffusion Coefficients (ADC) and areas under the time-intensity perfusion curve (AUC) were compared with the histologic necrosis ratio, fibrosis, and cellularity in post-surgical specimens. Results: We retrieved 29 patients. The median ADC value was 134.3 × 10 -3 mm 2 /s. ADC values positively correlated with the post-treatment tumor necrosis ratio ( p = 0.013). Median ADC values were lower in patients with less than 50% necrosis and higher in those with more than 50% (120.3 × 10 -3 mm 2 /s and 202.0 × 10 -3 mm 2 /s, respectively ( p = 0.020). ADC values higher than 161 × 10 -3 mm 2 /s presented a 95% sensitivity and a 55% specificity for the identification of tumors with more than 50% tumor necrosis ratio. Tumor-to-muscle AUC ratios were associated with histologic fibrosis ( p = 0.036). Conclusions: ADC and perfusion AUC correlated, respectively, with radiation-induced tumor necrosis and fibrosis.

Background: Multidisciplinary management is crucial in cancer diagnosis and treatment. Multidisciplinary teams include specialists in surgery, medical therapies, and radiation therapy (RT), each playing unique roles in oncology care. One significant aspect is RT, guided by radiation oncologists (ROs). This paper serves as a detailed primer for non-oncologists, medical students, or non-clinical investigators, educating them on contemporary RT practices. Methods: This report follows the process of RT planning and execution. Starting from the decision-making in multidisciplinary teams to the completion of RT and subsequent patient follow-up, it aims to offer non-oncologists an understanding of the RO's work in a comprehensive manner. Results: The first step in RT is a planning session that includes obtaining a CT scan of the area to be treated, known as the CT simulation. The patients are imaged in the exact position in which they will receive treatment. The second step, which is the primary source of uncertainty, involves the delineation of treatment targets and organs at risk (OAR). The objective is to ensure precise irradiation of the target volume while sparing the OARs as much as possible. Various radiation modalities, such as external beam therapy with electrons, photons, or particles (including protons and carbon ions), as well as brachytherapy, are utilized. Within these modalities, several techniques, such as three-dimensional conformal RT, intensity-modulated RT, volumetric modulated arc therapy, scattering beam proton therapy, and intensity-modulated proton therapy, are employed to achieve optimal treatment outcomes. The RT plan development is an iterative process involving medical physicists, dosimetrists, and ROs. The complexity and time required vary, ranging from an hour to a week. Once approved, RT begins, with image-guided RT being standard practice for patient alignment. The RO manages acute toxicities during treatment and prepares a summary upon completion. There is a considerable variance in practices, with some ROs offering lifelong follow-up and managing potential late effects of treatment. Conclusions: Comprehension of RT clinical effects by non-oncologists providers significantly elevates long-term patient care quality. Hence, educating non-oncologists enhances care for RT patients, underlining this report's importance.

Background: The purpose of this study was to evaluate the clinical, biological and radiological responses to, and tolerability of, conventional transarterial chemoembolization (cTACE) using streptozocin for unresectable neuroendocrine liver metastases., Patients and Methods: A total of 52 patients with predominant liver disease were treated with cTACE using an emulsion of streptozocin, Lipiodol and embolization particles. A sequential approach was favored in patients with high liver tumor burden. Clinical, biological and radiological responses were evaluated using carcinoid symptoms, biomarkers and mRecist criteria, respectively., Results: A total of 127 procedures were performed with a sequential approach in 65% of patients. All patients received streptozocin and Lipiodol. Carcinoid syndrome was improved in 69% of patients after treatment ( p = 0.01). Post-embolization syndrome was reported in 78% of patients. At the end of all cTACE, objective response and non-progressive disease were 32% and 70%, respectively. Progression-free survival was 18.3 ± 13.3 months (median 14.9) and median overall survival (OS) from start of treatment was 74 months. The OS at 1 year, 2 years, 3 years and 5 years was 91% (IC = 84-99%), 84% (CI = 72-95%), 69% (CI = 53-84%) and 63% (C = 46-81%), respectively., Conclusions: cTACE using streptozocin is an effective and well-tolerated palliative option for patients with neuroendocrine liver metastases, associated with prolonged survival and delayed time to progression.

Stereotactic body radiation therapy (SBRT) has made the hypofractionation of high doses delivered in a few sessions more acceptable. While the benefits of hypofractionated SBRT have been attributed to additional vascular, immune effects, or specific cell deaths, a radiobiological and mechanistic model is still needed. By considering each session of SBRT, the dose is divided into hundreds of minibeams delivering some fractions of Gy. In such a dose range, the hypersensitivity to low dose (HRS) phenomenon can occur. HRS produces a biological effect equivalent to that produced by a dose 5-to-10 times higher. To examine whether HRS could contribute to enhancing radiation effects under SBRT conditions, we exposed tumor cells of different HRS statuses to SBRT. Four human HRS-positive and two HRS-negative tumor cell lines were exposed to different dose delivery modes: a single dose of 0.2 Gy, 2 Gy, 10 × 0.2 Gy, and a single dose of 2 Gy using a non-coplanar isocentric minibeams irradiation mode were delivered. Anti- γH2AX immunofluorescence, assessing DNA double-strand breaks (DSB), was applied. In the HRS-positive cells, the DSB produced by 10 × 0.2 Gy and 2 Gy, delivered by tens of minibeams, appeared to be more severe, and they provided more highly damaged cells than in the HRS-negative cells, suggesting that more severe DSB are induced in the "SBRT modes" conditions when HRS occurs in tumor. Each SBRT session can be viewed as hyperfractionated dose delivery by means of hundreds of low dose minibeams. Under current SBRT conditions (i.e., low dose per minibeam and not using ultra-high dose-rate), the response of HRS-positive tumors to SBRT may be enhanced significantly. Interestingly, similar conclusions were reached with HRS-positive and HRS-negative untransformed fibroblast cell lines, suggesting that the HRS phenomenon may also impact the risk of post-RT tissue overreactions.

Background: Knowledge about the precise effects of radiotherapy on hypothalamo-pituitary functions is limited. Reduction of side effects is a major goal of advanced radiotherapy modalities. We assessed strategies for monitoring and replacement of hormone deficiencies in irradiated patients., Methods: A search strategy was systematically conducted on PubMed ® . Additional articles were retrieved to describe endocrine mechanisms., Results: 45 studies were evaluated from 2000 to 2022. They were predominantly retrospective and highly heterogeneous concerning patient numbers, tumor types, radiotherapy technique and follow-up. Endocrine deficiencies occurred in about 40% of patients within a median follow-up of 5.6 years without a clear difference between radiotherapy modalities. Somatotropic and thyrotropic axes were, respectively, the most and least radiosensitive., Conclusions: Current pituitary gland dose constraints may underestimate radiation-induced endocrine deficiencies, thus impairing quality of life. Little difference might be expected between radiation techniques for PG tumors. For non-PG tumors, dose constraints should be applied more systematically., Competing Interests: The authors declare no conflict of interest. The funder had no role in the study's design; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Introduction: Segmentation of organs at risk (OARs) and target volumes need time and precision but are highly repetitive tasks. Radiation oncology has known tremendous technological advances in recent years, the latest being brought by artificial intelligence (AI). Despite the advantages brought by AI for segmentation, some concerns were raised by academics regarding the impact on young radiation oncologists' training. A survey was thus conducted on young french radiation oncologists (ROs) by the SFjRO (Société Française des jeunes Radiothérapeutes Oncologues)., Methodology: The SFjRO organizes regular webinars focusing on anatomical localization, discussing either segmentation or dosimetry. Completion of the survey was mandatory for registration to a dosimetry webinar dedicated to head and neck (H & N) cancers. The survey was generated in accordance with the CHERRIES guidelines. Quantitative data (e.g., time savings and correction needs) were not measured but determined among the propositions., Results: 117 young ROs from 35 different and mostly academic centers participated. Most centers were either already equipped with such solutions or planning to be equipped in the next two years. AI segmentation software was mostly useful for H & N cases. While for the definition of OARs, participants experienced a significant time gain using AI-proposed delineations, with almost 35% of the participants saving between 50-100% of the segmentation time, time gained for target volumes was significantly lower, with only 8.6% experiencing a 50-100% gain. Contours still needed to be thoroughly checked, especially target volumes for some, and edited. The majority of participants suggested that these tools should be integrated into the training so that future radiation oncologists do not neglect the importance of radioanatomy. Fully aware of this risk, up to one-third of them even suggested that AI tools should be reserved for senior physicians only., Conclusions: We believe this survey on automatic segmentation to be the first to focus on the perception of young radiation oncologists. Software developers should focus on enhancing the quality of proposed segmentations, while young radiation oncologists should become more acquainted with these tools.

Chondrosarcoma is a malignant cartilaginous tumor that is particularly chemoresistant and radioresistant to X-rays. The first line of treatment is surgery, though this is almost impossible in some specific locations. Such resistances can be explained by the particular composition of the tumor, which develops within a dense cartilaginous matrix, producing a resistant area where the oxygen tension is very low. This microenvironment forces the cells to adapt and dedifferentiate into cancer stem cells, which are described to be more resistant to conventional treatments. One of the main avenues considered to treat this type of tumor is hadrontherapy, in particular for its ballistic properties but also its greater biological effectiveness against tumor cells. In this review, we describe the different forms of chondrosarcoma resistance and how hadrontherapy, combined with other treatments involving targeted inhibitors, could help to better treat high-grade chondrosarcoma., Competing Interests: The authors declare no conflicts of interest.

Background: The impact of several non-clinical factors on cancer survival is poorly understood. The aim of this study was to investigate the influence of travel time to the nearest referral center on survival of patients with cancer., Patients and Methods: The study used data from the French Network of Cancer Registries that combines all the French population-based cancer registries. For this study, we included the 10 most common solid invasive cancer sites in France between 1 January 2013 and 31 December 2015, representing 160,634 cases. Net survival was measured and estimated using flexible parametric survival models. Flexible excess mortality modelling was performed to investigate the association between travel time to the nearest referral center and patient survival. To allow the most flexible effects, restricted cubic splines were used to investigate the influence of travel times to the nearest cancer center on excess hazard ratio., Results: Among the 1-year and 5-year net survival results, lower survival was observed for patients residing farthest from the referral center for half of the included cancer types. The remoteness gap in survival was estimated to be up to 10% at 5 years for skin melanoma in men and 7% for lung cancer in women. The pattern of the effect of travel time was highly different according to tumor type, being either linear, reverse U-shape, non-significant, or better for more remote patients. For some sites restricted cubic splines of the effect of travel time on excess mortality were observed with a higher excess risk ratio as travel time increased., Conclusions: For numerous cancer sites, our results reveal geographical inequalities, with remote patients experiencing a worse prognosis, aside from the notable exception of prostate cancer. Future studies should evaluate the remoteness gap in more detail with more explanatory factors.

Everolimus is the first oral targeted therapy widely used in advanced HR+/HER2- breast cancer. We sought to evaluate the impact of everolimus-based therapy on overall survival in the ESME-MBC database, a national metastatic breast cancer cohort that collects retrospective data using clinical trial-like methodology including quality assessments. We compared 1693 patients having received everolimus to 5928 patients not exposed to everolimus in the same period. Overall survival was evaluated according to treatment line, and a propensity score with the inverse probability of treatment weighting method was built to adjust for differences between groups. Crude and landmark overall survival analyses were all compatible with a benefit from everolimus-based therapy. Adjusted hazard ratios for overall survival were 0.34 (95% CI: 0.16-0.72, p = 0.0054), 0.34 (95% CI: 0.22-0.52, p < 0.0001), and 0.23 (95% CI: 0.14-0.36, p < 0.0001) for patients treated with everolimus in line 1, 2, and 3 and beyond, respectively. No clinically relevant benefit on progression-free survival was observed. Causes for everolimus discontinuation were progressive disease (56.2%), adverse events (27.7%), and other miscellaneous reasons. Despite the limitations inherent to such retrospective studies, these results suggest that adding everolimus-based therapy to the therapeutic sequences in patients with advanced HR+/HER2- breast cancer may favorably affect overall survival., Competing Interests: JSF declares consulting fees from Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, Seagen, Exact Science; honoraria for lectures from Lilly, Novartis, Gilead, Daiichi Sankyo, Seagen; travel support and meeting attendance from Pfizer, Milly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, Seagen. AG declares Institutional research funding from MSD, BMS, Novartis, Boehringer Ingelheim, Roche Genentech, AstraZeneca, Sanofi, and Daiichi Sankyo. PC declares consulting fees and honoraria from Pfizer, Roche, Lilly; Institutional research funding from Novartis, Pfizer; travel support and meeting attendance from Roche, Pfizer, and Daiichi Sankyo. All other authors declare no conflicts of interest.

Background: In cancer net survival analyses, if life tables (LT) are not stratified based on socio-demographic characteristics, then the social gradient in mortality in the general population is ignored. Consequently, the social gradient estimated on cancer-related excess mortality might be inaccurate. We aimed to evaluate whether the social gradient in cancer net survival observed in France could be attributable to inaccurate LT., Methods: Deprivation-specific LT were simulated, applying the social gradient in the background mortality due to external sources to the original French LT. Cancer registries' data from a previous French study were re-analyzed using the simulated LT. Deprivation was assessed according to the European Deprivation Index (EDI). Net survival was estimated by the Pohar-Perme method and flexible excess mortality hazard models by using multidimensional penalized splines., Results: A reduction in net survival among patients living in the most-deprived areas was attenuated with simulated LT, but trends in the social gradient remained, except for prostate cancer, for which the social gradient reversed. Flexible modelling additionally showed a loss of effect of EDI upon the excess mortality hazard of esophagus, bladder and kidney cancers in men and bladder cancer in women using simulated LT., Conclusions: For most cancers the results were similar using simulated LT. However, inconsistent results, particularly for prostate cancer, highlight the need for deprivation-specific LT in order to produce accurate results.

(1) Background: radiotherapy is a cornerstone of cancer treatment. When delivering a tumoricidal dose, the risk of severe late toxicities is usually kept below 5% using dose-volume constraints. However, individual radiation sensitivity (iRS) is responsible (with other technical factors) for unexpected toxicities after exposure to a dose that induces no toxicity in the general population. Diagnosing iRS before radiotherapy could avoid unnecessary toxicities in patients with a grossly normal phenotype. Thus, we reviewed iRS diagnostic data and their impact on decision-making processes and the RT workflow; (2) Methods: following a description of radiation toxicities, we conducted a critical review of the current state of the knowledge on individual determinants of cellular/tissue radiation; (3) Results: tremendous advances in technology now allow minimally-invasive genomic, epigenetic and functional testing and a better understanding of iRS. Ongoing large translational studies implement various tests and enriched NTCP models designed to improve the prediction of toxicities. iRS testing could better support informed radiotherapy decisions for individuals with a normal phenotype who experience unusual toxicities. Ethics of medical decisions with an accurate prediction of personalized radiotherapy's risk/benefits and its health economics impact are at stake; (4) Conclusions: iRS testing represents a critical unmet need to design personalized radiotherapy protocols relying on extended NTCP models integrating iRS.

Oncological strategies in the elderly population are debated. The objective of this study was to determine the predictive factors of survival in patients aged 80 years and older with metastatic colon cancer. Data from four digestive tumour registry databases were used in this analysis. This population-based retrospective study included 1115 patients aged 80 years and older with stage IV colon adenocarcinoma diagnosed between 2007 and 2016. Cox regression was used to assess the impact of different prognostic factors. Age was significantly correlated with the surgical treatment (p < 0.001) but not with overall survival. Patients with a low comorbidity burden had better survival than patients with higher comorbidities scores (9.4 (0−123) versus 7.9 (0−115) months) (p = 0.03). Surgery was more common for proximal colon cancer (p < 0.001), but the location of the primary lesion was not correlated with improved survival (p = 0.07). Patients with lung metastases had a better prognosis than those with liver metastases (HR 0.56 95% CI 0.40, 0.77 p < 0.001); multiple organ involvement had the worst survival (HR 1.32 95% CI 1.15, 1.51 p < 0.001). Chemotherapy was associated with improved survival for both operated (HR 0.45 95% CI 0.35, 0.58 p < 0.001) and non-operated patients (HR 0.41 95% CI 0.34, 0.50 p < 0.001). The majority of patients receiving adjuvant treatment had a low comorbidity burden. In our study, the location of metastases but not the primary tumor location had an impact on overall survival. Low comorbidity burden, curative surgery, and chemotherapy had a significant advantage for elderly patients with metastatic colon cancer.

Chemotherapy-related cognitive impairment (CRCI) and fatigue constitute common complaints among cancer patient survivors. Panax quinquefolius has been shown to be effective against fatigue in treated cancer patients. We developed a behavioral C57Bl/6j mouse model to study the role of a Panax quinquefolius -based solution containing vitamin C (Qiseng ® ) or vitamin C alone in activity/fatigue, emotional reactivity and cognitive functions impacted by 5-Fluorouracil (5-FU) chemotherapy. 5-FU significantly reduces the locomotor/exploration activity potentially associated with fatigue, evokes spatial cognitive impairments and leads to a decreased neurogenesis within the hippocampus (Hp). Qiseng ® fully prevents the impact of chemotherapy on activity/fatigue and on neurogenesis, specifically in the ventral Hp. We observed that the chemotherapy treatment induces intestinal damage and inflammation associated with increased levels of Lactobacilli in mouse gut microbiota and increased expression of plasma pro-inflammatory cytokines, notably IL-6 and MCP-1. We demonstrated that Qiseng ® prevents the 5-FU-induced increase in Lactobacilli levels and further compensates the 5-FU-induced cytokine release. Concomitantly, in the brains of 5-FU-treated mice, Qiseng ® partially attenuates the IL-6 receptor gp130 expression associated with a decreased proliferation of neural stem cells in the Hp. In conclusion, Qiseng ® prevents the symptoms of fatigue, reduced chemotherapy-induced neuroinflammation and altered neurogenesis, while regulating the mouse gut microbiota composition, thus protecting against intestinal and systemic inflammation.

Background: In spite of the frequency and clinical impact of BRCA1/2 alterations in high-grade epithelial ovarian cancer (HGEOC), real-world information based on robust data warehouse has been scarce to date., Methods: Consecutive patients with BRCA -mutated HGEOC treated between 2011 and 2016 within French comprehensive cancer centers from the Unicancer network were extracted from the ESME database. The main objective of the study was the assessment of clinicopathological and treatments parameters., Results: Out of the 8021 patients included in the ESME database, 266 patients matching the selection criteria were included. BRCA1 mutation was found in 191 (71.8%) patients, while 75 (28.2%) had a BRCA2 mutation only; 95.5% of patients received a cytoreductive surgery. All patients received a taxane/platinum-based chemotherapy (median = six cycles). Complete and partial response were obtained in 53.3% and 20.4% of the cases, respectively. Maintenance therapy was administered in 55.3% of the cases, bevacizumab being the most common agent. After a median follow up of 51.7 months, a median progression-free survival of 28.6 months (95% confidence interval (CI) [26.5; 32.7]) and an estimated 5-year median overall survival of 69.2% (95% CI [61.6; 70.3]) were reported. Notably, BRCA1 - and BRCA2 -mutated cases exhibited a trend towards different median progression-free survivals, with 28.0 (95% CI [24.4; 32.3]) and 33.3 months (95% CI [26.7; 46.1]), respectively ( p -value = 0.053). Furthermore, five-year OS for BRCA1 -mutated patients was 64.5% (95% CI [59.7; 69.2]), while it was 82.5% (95% CI [76.6; 88.5]) for BRCA2 -mutated ones ( p -value = 0.029)., Conclusions: This study reports the largest French multicenter cohort of BRCA -mutated HGEOCs based on robust data from the ESME, exhibiting relevant real-world data regarding this specific population.

Inflammatory breast cancer (IBC) is a rare entity with a poor prognosis. We analysed the survival outcomes of patients with nonmetastatic IBC and the prognostic value of tumour or nodal responses to assess their individual prognostic impact across IBC subtypes. This retrospective multicentre study included patients diagnosed with IBC between 2010 and 2017 to account for advances in neoadjuvant systemic therapies and modern radiotherapy at seven oncology centres in France. Three hundred and seventeen patients were included and analysed. After a median follow-up of 52 months, the 5-year DFS was lower for triple-negative (TN) (50.1% vs. 63.6%; p < 0.0001). After multivariate analyses, incomplete nodal response was the only significant prognostic factor in the triple-negative group (HR:6.06). The poor prognosis of TN-IBC was reversed in the case of nodal response after neoadjuvant chemotherapy. Breast response does not appear to be a decisive prognostic factor in patients with TN-IBC compared to lymph node response. Despite improvements in neoadjuvant treatments, IBC remains associated with a poor prognosis. In TN-IBC patients, lack of pathological complete node response was associated with poorer survival than any other group. Treatment intensification strategies are worth investigating.

Survival in unresectable locally advanced stage non-small cell lung cancer (NSCLC) patients remains poor despite chemoradiotherapy. Recently, adjuvant immunotherapy improved survival for these patients but we are still far from curing most of the patients with only a 57% survival remaining at 3 years. This poor survival is due to the resistance to chemoradiotherapy, local relapses, and distant relapses. Several biological mechanisms have been found to be involved in the chemoradioresistance such as cancer stem cells, cancer mutation status, or the immune system. New drugs to overcome this radioresistance in NSCLCs have been investigated such as radiosensitizer treatments or immunotherapies. Different modalities of radiotherapy have also been investigated to improve efficacity such as dose escalation or proton irradiations. In this review, we focused on biological mechanisms such as the cancer stem cells, the cancer mutations, the antitumor immune response in the first part, then we explored some strategies to overcome this radioresistance in stage III NSCLCs with new drugs or radiotherapy modalities.

The national reference network NETSARC+ provides remote access to specialized diagnosis and the Multidisciplinary Tumour Board (MTB) to improve the management and survival of sarcoma patients in France. The IGéAS research program aims to assess the potential of this innovative organization to address geographical inequalities in cancer management. Using the IGéAS cohort built from the nationwide NETSARC+ database, the individual, clinical, and geographical determinants of the 3-year overall survival of sarcoma patients in France were analyzed. The survival analysis was focused on patients diagnosed in 2013 (n = 2281) to ensure sufficient hindsight to collect patient follow-up. Our study included patients with bone (16.8%), soft-tissue (69%), and visceral (14.2%) sarcomas, with a median age of 61.8 years. The overall survival was not associated with geographical variables after adjustment for individual and clinical factors. The lower survival in precarious population districts [HR 1.23, 95% CI 1.02 to 1.48] in comparison to wealthy metropolitan areas (HR = 1) found in univariable analysis was due to the worst clinical presentation at diagnosis of patients. The place of residence had no impact on sarcoma patients' survival, in the context of the national organization driven by the reference network. Following previous findings, this suggests the ability of this organization to go through geographical barriers usually impeding the optimal management of cancer patients.

Population-based studies provide the opportunity to assess the real-world applicability of current clinical practices. The present research evaluated the survival outcomes of different therapeutic strategies for colorectal cancer (CRC) with synchronous metastasis (SM). The differential impact of treatment sequence, viz. whether chemotherapy (CT) or primary tumor resection (PTR) was performed first, was also evaluated., Methods: All CRC cases with SM diagnosed between 2006 and 2016 ( N = 3062) were selected from two specialized digestive cancer registries from northwest France. Cox regression analysis was used to assess survival. Multivariable logistic regression was used to examine factors related to the combination of PTR and CT., Results: The longest survival was observed in patients treated by PTR combined with CT (Group 4; N = 1159). Overall survival was 51.80% at one year (95% Confidence Interval (CI) 50.00-53.60%) and 9.40% at five years (95% CI, 8.30-10.60%). Survival did not differ with respect to the order of treatment in multivariable analysis (hazard ratio, 1.05; 95% CI, 0.88-1.24; p = 0.55)., Conclusion: Regardless of the sequence of treatment, a PTR + CT offered the best survival in patients with CRC and SM, even though few were eligible for combination therapy (38%).

Brigatinib is a next-generation ALK inhibitor (ALKi) that shows efficacy in ALK inhibitor naïve and post-crizotinib ALK+ advanced NSCLCs (aNSCLCs). The efficacy of brigatinib was retrospectively assessed in patients with aNSCLCs included in the brigatinib French Early-Access Program (1 August 2016−21 January 2019). The primary endpoint was investigator-assessed progression-free survival (invPFS) and the primary analysis was updated in 2021 with a longer follow-up, focused on post-brigatinib lorlatinib efficacy. Sixty-six centers included 183 patients: median age 60 ± 12.7 years; 78.3% never/former smokers; median of 3 ± 1 previous lines and 2 ± 0.5 ALKis; 37.1% ECOG PS 2 and 55.6% >3 metastatic sites. The median follow-up from brigatinib initiation was 40.4 months (95% CI 38.4−42.4). InvPFS was 7.4 months (95% CI 5.9−9.6), median duration of treatment (mDOT) was 7.3 months (95% CI 5.8−9.4) and median overall survival (mOS) was 20.3 months (95% CI 15.6−27.6). The median DOT and OS from brigatinib initiation tend to decrease with the number of ALK inhibitors used in previous lines of therapy. Based on the data collected, 92 (50.3%) patients received ≥1 agent(s) post-brigatinib and 68 (73.9%) of them received lorlatinib, with 51 (75%) immediately receiving it post-brigatinib, 12 (17.6%) receiving it after one and 5 (7.4%) after ≥2 subsequent treatments. The median follow-up was 29.9 (95% CI 25.7−33.1) months. Lorlatinib mDOT was 5.3 (95% CI 3.6−7.6) months with a median OS from lorlatinib initiation of 14.1 (95% CI 10.3−19.2) months. The results of the brigALK2 study confirm the efficacy of brigatinib in a population of heavily pretreated ALK+ aNSCLC patients and provide new data on the activity of lorlatinib after brigatinib.

Background: Gynecological carcinosarcomas are rare and aggressive diseases, with a poor prognosis. The rarity of these tumors explains the lack of robust and specific data available in the literature. The objective of this study was to investigate the impact of initial adjuvant treatment and recurrent therapeutic strategies., Patients and Methods: A multicentric cohort study within the French national prospective Rare Malignant Gynecological Tumors (TMRG) network was conducted. Data from all included carcinosarcomas diagnosed between 2011 and 2018 were retrospectively collected., Results: 425 cases of uterine and ovarian carcinosarcomas ( n = 313 and n = 112, respectively) were collected and analyzed from 12 participating centers. At diagnosis, 140 patients (48%) had a FIGO stage III-IV uterine carcinosarcoma (UCS) and 88 patients (83%) had an advanced ovarian carcinosarcoma (OCS) (FIGO stage ≥ III). Two hundred sixty-seven patients (63%) received adjuvant chemotherapy, most preferably carboplatin-paclitaxel regimen ( n = 227, 86%). After a median follow-up of 47.4 months, the median progression-free survival (mPFS) was 15.1 months (95% CI 12.3-20.6) and 14.8 months (95% CI 13.1-17.1) for OCS and UCS, respectively. The median overall survival for OCS and UCS was 37.1 months (95% CI 22.2-49.2) and 30.6 months (95% CI 24.1-40.9), respectively. With adjuvant chemotherapy followed by radiotherapy, mPFS was 41.0 months (95% CI 17.0-NR) and 18.9 months (95% CI 14.0-45.6) for UCS stages I-II and stages III-IV, respectively. In the early stage UCS subgroup (i.e., stage IA, n = 86, 30%), mPFS for patients treated with adjuvant chemotherapy ( n = 24) was not reached (95% CI 22.2-NR), while mPFS for untreated patients ( n = 62) was 19.9 months (95% IC 13.9-72.9) (HR 0.44 (0.20-0.95) p = 0.03). At the first relapse, median PFS for all patients was 4.2 months (95% CI 3.5-5.3). In the first relapse, mPFS was 6.7 months (95% CI 5.1-8.5) and 2.2 months (95% CI 1.9-2.9) with a combination of chemotherapy or monotherapy, respectively ( p < 0.001)., Conclusions: Interestingly, this vast prospective cohort of gynecological carcinosarcoma patients from the French national Rare Malignant Gynecological Tumors network (i) highlights the positive impact of adjuvant CT on survival in all localized stages (including FIGO IA uterine carcinosarcomas), (ii) confirms the importance of platinum-based combination as an option for relapse setting, and (iii) reports median PFS for various therapeutic strategies in the relapse setting.

Older cancer patients are vulnerable to chemotherapy-related cognitive impairment. We prospectively evaluated cognitive impairment and its predictive factors during first-line chemotherapy in elderly cancer patients (≥70 years). Cognitive function was evaluated by the Mini-Mental State Examination (MMSE) with adjusted scores for age and sociocultural level. Multidimensional geriatric assessment was performed at baseline and during chemotherapy including the MMSE, Instrumental Activities in Daily Living (IADL), Mini-Nutritional Assessment (MNA), and the Geriatric Depression Scale (GDS15). Quality of life (QoL) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire (QLQ-C30). Of 364 patients included, 310 had two MMSE evaluations including one at baseline and were assessed. Among these patients, 86 (27.7%) had abnormal MMSE, 195 (62.9%) abnormal MNA, 223 (71.9%) abnormal IADL, and 137 (43.1%) had depressive symptoms at baseline. MMSE impairment during chemotherapy was observed in 58 (18.7%) patients. Abnormal baseline MNA (odds ratio (OR) = 1.87, p = 0.021) and MMSE (OR = 2.58, p = 0.022) were independent predictive factors of MMSE impairment. These results suggest that pre-existing cognitive impairment and malnutrition are predictive factors for cognitive decline during chemotherapy in elderly cancer patients. Detection and management of these risk factors should be systematically considered in this population before starting chemotherapy.

Social inequalities are an important prognostic factor in cancer survival, but little is known regarding digestive cancers specifically. We aimed to provide in-depth analysis of the contextual social disparities in net survival of patients with digestive cancer in France, using population-based data and relevant modeling. Digestive cancers ( n = 54,507) diagnosed between 2006-2009, collected through the French network of cancer registries, were included (end of follow-up 30 June 2013). Social environment was assessed by the European Deprivation Index. Multidimensional penalized splines were used to model excess mortality hazard. We found that net survival was significantly worse for individuals living in a more deprived environment as compared to those living in a less deprived one for esophageal, liver, pancreatic, colon and rectal cancers, and for stomach and bile duct cancers among females. Excess mortality hazard was up to 57% higher among females living in the most deprived areas (vs. least deprived) at 1 year of follow-up for bile duct cancer, and up to 21% higher among males living in the most deprived areas (vs. least deprived) regarding colon cancer. To conclude, we provide a better understanding of how the (contextual) social gradient in survival is constructed, offering new perspectives for tackling social inequalities in digestive cancer survival.

Cancer-related cognitive impairment (CRCI) occurs frequently in patients living with cancer, with consequences on quality of life. Recently, research on the management of these difficulties has focused on computerized cognitive stimulation and computerized physical activity programs. This systematic review presents the state of knowledge about interventions based on computerized-cognitive stimulation and/or physical activity to reduce CRCI. The review followed the PRISMA guidelines. A search was conducted in PUBMED and Web of Science databases. Risk of bias analysis was conducted using the Rob2 tool and the quality of evidence was conducted following the GRADE approach. A total of 3776 articles were initially identified and 20 of them met the inclusion criteria. Among them, sixteen investigated computerized-cognitive stimulation and four computerized-physical activity. Most of the studies were randomized controlled trials and assessed the efficacy of a home-based intervention on objective cognition in adults with cancer. Overall, cognitive improvement was found in 11/16 computerized-cognitive stimulation studies and 2/4 computerized-physical activity studies. Cognitive stimulation or physical activity improved especially cognitive complaints, memory, and attention. These results suggest the efficacy of both computerized-cognitive stimulation and physical activity. However, we report a high risk of bias for the majority of studies and a low level of quality of evidence. Therefore, further investigations are needed to confirm the efficacy of these interventions and to investigate the possible added benefit on cognition of a combined computerized-cognitive/physical intervention.

Cancer-related cognitive impairment (CRCI) is a frequent side-effect of cancer treatment, with important consequences on patients' quality of life. Cognitive stimulation and physical activity are the most efficient in improving cognitive impairment, but they are challenging to generalize in hospitals' routine and to patients' needs and schedules. Moreover, the added value of a combination of these interventions needs to be more investigated. The Cog-Stim study is an interventional study investigating the feasibility of a web-based multimodal intervention (combining cognitive stimulation and physical activity for the improvement of cognitive complaints among breast-cancer patients currently treated with radiotherapy ( n = 20). Patients will take part in a 12-week program, proposing two sessions per week of web-based cognitive stimulation (20 min/session with HappyNeuron ® ) and two sessions per week of web-based physical activity (30 min/session with Mooven ® platform). Cognitive complaints (FACT-Cog) and objective cognitive functioning (CNS Vital Signs ® ), anxiety, depression (HADS), sleep disorders (ISI) and fatigue (FACIT-Fatigue) will be assessed before and after the intervention. The primary endpoint is the adherence rate to the intervention program. Patients' satisfaction, reasons for non-attrition and non-adherence to the program will also be assessed. The overall goal of this study is to collect information to develop web-based interventions for cognitive difficulties in supportive care units.

Background: France implemented in 2004 the French National Breast Cancer Screening Programme (FNBCSP). Despite national recommendations, this programme coexists with non-negligible opportunistic screening practices., Aim: Analyse socio-territorial inequities in the 2013-2014 FNBCSP campaign in a large sample of the eligible population., Method: Analyses were performed using three-level hierarchical generalized linear model. Level one was a 10% random sample of the eligible population in each département ( n = 397,598). For each woman, age and travel time to the nearest accredited radiology centre were computed. These observations were nested within 22,250 residential areas called "Îlots Regroupés pour l'Information Statistique" (IRIS), for which the European Deprivation Index (EDI) is defined. IRIS were nested within 41 départements , for which opportunistic screening rates and gross domestic product based on purchasing power parity were available, deprivation and the number of radiology centres for 100,000 eligible women were computed., Results: Organized screening uptake increased with age (OR 1SD = 1.05 [1.04-1.06]) and decreased with travel time (OR 1SD = 0.94 [0.93-0.95]) and EDI (OR 1SD = 0.84 [0.83-0.85]). Between départements , organized screening uptake decreased with opportunistic screening rate (OR 1SD = 0.84 [0.79-0.87]) and départements deprivation (OR 1SD = 0.91 [0.88-0.96]). Association between EDI and organized screening uptake was weaker as opportunistic screening rates and as département deprivation increased. Heterogeneity in FNBCSP participation decreased between IRIS by 36% and between départements by 82%., Conclusion: FNBCSP does not erase socio-territorial inequities. The population the most at risk of dying from breast cancer is thus the less participating. More efforts are needed to improve equity.

Assessment of age-dependent cancer risk for carriers of a predicted pathogenic variant (PPV) is often hampered by biases in data collection, with a frequent under-representation of cancer-free PPV carriers. TUMOSPEC was designed to estimate the cumulative risk of cancer for carriers of a PPV in a gene that is usually tested in a hereditary breast and ovarian cancer context. Index cases are enrolled consecutively among patients who undergo genetic testing as part of their care plan in France. First- and second-degree relatives and cousins of PPV carriers are invited to participate whether they are affected by cancer or not, and genotyped for the familial PPV. Clinical, family and epidemiological data are collected, and all data including sequencing data are centralized at the coordinating centre. The three-year feasibility study included 4431 prospective index cases, with 19.1% of them carrying a PPV. When invited by the coordinating centre, 65.3% of the relatives of index cases (5.7 relatives per family, on average) accepted the invitation to participate. The study logistics were well adapted to clinical and laboratory constraints, and collaboration between partners (clinicians, biologists, coordinating centre and participants) was smooth. Hence, TUMOSPEC is being pursued, with the aim of optimizing clinical management guidelines specific to each gene.

Cognitive side effects after cancer treatment threatening quality of life (QoL) constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are examples of next-generation therapy (NGT) administered to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment were reported. We developed a behavioral 17 months-aged and castrated mouse model receiving per os AAP or ENZ for 5 days per week for six consecutive weeks. ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH + -DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus highlighted ENZ-induced dopaminergic regulation within the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN + -neurons in the dorsal hippocampus. The consequences of the mCRPC treatment ENZ on aged castrated mouse motivation to exploration and cognition should make reconsider management strategy of elderly prostate cancer patients.

Radiation therapy (RT), either alone or in combination with surgery and/or chemotherapy is a keystone of cancers treatment. Early toxicity is common, sometimes leading to discontinuation of treatment. Recent studies stressed the role of the phosphorylated ATM (pATM) protein in RT-toxicity genesis and its ability in predicting individual radiosensitivity (IRS) in fibroblasts. Here we assessed the reliability of the pATM quantification in lymphocytes to predict IRS. A first retrospective study was performed on 150 blood lymphocytes of patients with several cancer types. Patients were divided into 2 groups, according to the grade of experienced toxicity. The global quantity of pATM molecules was assessed by ELISA on lymphocytes to determine the best threshold value. Then, the binary assay was assessed on a validation cohort of 36 patients with head and neck cancers. The quantity of pATM molecules in each sample of the training cohort was found in agreement with the observed Common Terminology Criteria for Adverse Events (CTCAE) grades with an AUC = 0.71 alone and of 0.77 combined to chemotherapy information. In the validation cohort, the same test was conducted with the following performances: sensitivity = 0.84, specificity = 0.54, AUC = 0.70 and 0.72 combined to chemotherapy. This study provides the basis of an easy to perform assay for clinical use.

Purpose: Management of head and neck cancers of unknown primary (HNCUP) combines neck dissection (ND) and radiotherapy, with or without chemotherapy. The prognostic value of ND has hardly been studied in HNCUP., Methods: A retrospective multicentric study assessed the impact of ND extent (adenectomy, selective ND, radical/radical-modified ND) on nodal relapse, progression-free survival (PFS) or survival, taking into account nodal stage., Results: 53 patients (16.5%) had no ND, 33 (10.2%) had lymphadenectomy, 116 (36.0%) underwent selective ND and 120 underwent radical/radical-modified ND (37.3%), 15 of which received radical ND (4.7%). With a 34-month median follow-up, the 3-year incidence of nodal relapse was 12.5% and progression-free survival (PFS) 69.1%. In multivariate analysis after adjusting for nodal stage, the risk of nodal relapse or progression was reduced with lymphadenectomy, selective or radical/modified ND, but survival rates were similar. Patients undergoing lymphadenectomy or ND had a better PFS and lowered nodal relapse incidence in the N1 + N2a group, but the improvement was not significant for the N2b or N2 + N3c patients. Severe toxicity rates exceeded 40% with radical ND., Conclusion: In HNCUP, ND improves PFS, regardless of nodal stage. The magnitude of the benefit of ND does not appear to depend on ND extent and decreases with a more advanced nodal stage.

Cognitive complaints are common adverse effects in cancer patients. Identifying subjects at risk could make it possible to limit their impact. We aimed to explore the relationship between current cognitive complaints and demographic and psychological factors in a group of breast cancer survivors. Through an online survey, cancer survivors reported current cognitive complaints using the FACT-Cog questionnaire (Perceived Cognitive Impairment) and answered questions about their demographics, lifestyle and cancer-related characteristics. Anxiety, depression, fatigue and post-traumatic stress symptoms were also assessed. We used multivariable logistic regression models to explore the relationships between current cognitive complaints and social and psychological factors. Among the 1393 breast cancer survivors, 47.2% ( n = 657) reported current cognitive complaints. Chemotherapy (OR = 2.26, 95%CI = 1.67-3.05), age (OR 21-44 vs. >65 = 0.14, 95%CI = 0.07-0.27), sleep difficulties (OR never vs. often = 2.41, 95%CI = 1.47-3.95), frequency of psychotropic treatments (OR never vs. >1/week = 1.70, 95%CI = 1.23-2.36), post-traumatic stress symptoms (OR = 2.05, 95%CI = 1.57-2.69) and employment status (OR full-time or part-time vs. sick leave = 1.64, 95%CI = 1.08-2.49) were strongly associated with current cognitive complaints. In this large study, about half of breast cancer survivors reported cognitive complaints, particularly after chemotherapy. Some risk factors should be detected early to reduce persistent cognitive complaints after cancer: mainly sleep difficulties, post-traumatic stress symptoms and psychotropic medications.

The purpose of this study was to determine the dynamic contributions of different immune cell subsets to primary and abscopal tumor regression after hypofractionated radiation therapy (hRT) and the impact of anti-PD-1 therapy. A bilateral syngeneic FSA1 fibrosarcoma model was used in immunocompetent C3H mice, with delayed inoculation to mimic primary and microscopic disease. The effect of tumor burden on intratumoral and splenic immune cell content was delineated as a prelude to hRT on macroscopic T1 tumors with 3 fractions of 8 Gy while microscopic T2 tumors were left untreated. This was performed with and without systemic anti-PD-1. Immune profiles within T1 and T2 tumors and in spleen changed drastically with tumor burden in untreated mice with infiltrating CD4+ content declining, while the proportion of CD4+ Tregs rose. Myeloid cell representation escalated in larger tumors, resulting in major decreases in the lymphoid:myeloid ratios. In general, activation of Tregs and myeloid-derived suppressor cells allow immunogenic tumors to grow, although their relative contributions change with time. The evidence suggests that primary T1 tumors self-regulate their immune content depending on their size and this can influence the lymphoid compartment of T2 tumors, especially with respect to Tregs. Tumor burden is a major confounding factor in immune analysis that has to be taken into consideration in experimental models and in the clinic. hRT caused complete local regression of primary tumors, which was accompanied by heavy infiltration of CD8+ T cells activated to express IFN-γ and PD-1; while certain myeloid populations diminished. In spite of this active infiltrate, primary hRT failed to generate the systemic conditions required to cause abscopal regression of unirradiated microscopic tumors unless PD-1 blockade, which on its own was ineffective, was added to the RT regimen. The combination further increased local and systemically activated CD8+ T cells, but few other changes. This study emphasizes the subtle interplay between the immune system and tumors as they grow and how difficult it is for local RT, which can generate a local immune response that may help with primary tumor regression, to overcome the systemic barriers that are generated so as to effect immune regression of even small abscopal lesions.

Survivors of early-stage breast cancer may report treatment-related side effects that persist for several years after the end of primary treatment. Among these, fatigue and cognitive disorders are frequent complaints and can negatively impact quality of life. Cancer-related fatigue is a very prevalent and distressing long-term side effect among breast cancer survivors that typically improves after completion of treatment, although many patients report severe fatigue several years post-treatment. Cognitive disorders are also common among survivors of breast cancer, especially if treated with chemotherapy. These symptoms are usually mild-to-moderate and often transient. Cognitive recovery is frequently observed within months or a few years after completion of chemotherapy or endocrine therapy. However, some breast cancer survivors may have persistent cognitive difficulties. Several types of interventions have proved to be beneficial in reducing cancer-related fatigue and cognitive difficulties. Most of these interventions for cancer-related fatigue are thought to be effective by reducing inflammation or disrupting pro-inflammatory circuits. Further studies are needed on cognitive management that has showed promising results. This narrative review summarizes the state of the art regarding long-term fatigue and cognitive disorders in patients with early breast cancer, describing prevalence, impact, pathophysiology, and risk factors, and focusing on available interventions., Competing Interests: I.V. L. received honoraria from Kephren, Novartis, A.-Z. A. D. M. received honoraria from Thermo-Fisher.