[Serious adverse effects with immunotherapies for the treatment of melanoma, non-small cell lung cancer, and renal cell carcinoma: Real-world evidence study]. / Effets indésirables graves des immunothérapies dans le traitement du mélanome, du cancer bronchique non à petites cellules et du carcinome à cellules rénales : étude en vie réelle.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a key component of standard anticancer systemic therapy. While their immune-related adverse effects (irAEs) have been widely described, there are few data on grade≥3 irAEs. The primary aim of our descriptive study was to evaluate their incidence and characteristics. METHODS: An observational, retrospective, monocentric study was conducted. It included patients with locally advanced or metastatic melanoma, non-small cell lung cancer or renal cell carcinoma who initiated ICI therapy between 2016-2021 and experienced at least one grade≥3 irAEs coded according to the MedDRA® system. RESULTS: All cancer types and ICIs combined, the incidence of grade≥3 irAEs was estimated at 11.7% [9.6-13.9]. These were mainly hepatobiliary (22%), gastrointestinal (17%), musculoskeletal (16%) and respiratory (16%) disorders. They occurred on average 6.2±6.2 months after the start of treatment, resulting in hospitalization or prolonged hospitalization in over 40 and 20% of cases, respectively. Resolution without sequelae was observed in 56% of cases, but four patients died. DISCUSSION: This real-world study investigated three cancers and several ICIs, unlike previously published studies that focused on a single cancer and/or one ICI. It provides a better understanding of grade≥3 irAEs, most of which are reversible, which an aim to optimize patient care.

Combination of radiotherapy and immunotherapy in duality with the protumoral action of radiation.

Radiotherapy is widely used to treat various cancers. Its combination with immune checkpoint inhibitors is intensively studied preclinically and clinically. Although the first results were very encouraging, the number of patients who respond positively remains low, and the therapeutic benefit is often temporary. This review summarizes how radiation can stimulate an antitumor immune response and its combination with immunotherapy based on inhibiting immune checkpoints. We will provide an overview of radiotherapy parameters that should be better controlled to avoid downregulating the antitumor immune response. The low response rate of combining radiotherapy and immunotherapy could, at least in part, be caused by the stimulation of cancer cell invasion and metastasis development that occur at similar doses and number of radiation fractions. To end on a positive note, we explore how a targeted inhibition of the inflammatory cytokines induced by radiation with a cyclooxygenase-2 inhibitor could both support an antitumor immune response and block radiation-induced metastasis formation.

[Targeted therapies and immunotherapy: Positioning in the field of innovation and challenges for the therapeutic decision-making process]. / Thérapies ciblées et immunothérapie : positionnement dans le champ de l'innovation et enjeux pour le processus de décision thérapeutique.

The better understanding of the molecular, cellular, and immunological mechanisms of cancer has led to the development of targeted therapies, then immunotherapy, which have changed the approach to cancer treatment. While these treatments differ from chemotherapy in their mechanisms of action, they also allow for increased personalization of cancer care through the development of technologies that target patients more precisely. However, they are associated with several challenges: the management of uncertainty associated with their risk-benefit balance due to the lack of long-term data and sometimes scientific evidence on their effects; the complexity of integrating molecular and immunological data into the therapeutic decision; the challenge of inequalities in access to these treatments often considered revolutionary due to the required molecular characterization and/or inclusion criteria for early-phase trials; and the challenge of their appropriation and adoption by physicians and patients. This narrative review explores each of these challenges in the context of shared decision-making, the promotion of which is a guarantee of quality and safety of care for cancer patients.

Outcomes of adjuvant lymph node field radiotherapy and immunotherapy for stage III melanoma.

PURPOSE: With the promising results of immunotherapy in patients with stage III melanoma, the role of adjuvant radiotherapy after resection and complete lymph-node dissection must be reassessed. We evaluate the outcomes and safety of adjuvant radiotherapy and immunotherapy compared to immunotherapy only in patients with resected stage III melanoma. PATIENTS AND METHODS: This retrospective and single institution study included patients treated for a stage III melanoma with complete lymph-node dissection and adjuvant immunotherapy from January 2019 to December 2022. The radiotherapy associated with immunotherapy group was defined by completion of immunotherapy and adjuvant radiotherapy in the lymph-node dissection area. The primary endpoint was disease-free survival. The secondary endpoints were locoregional progression, incidence of adverse events grade 3 or above and disease-free survival rate in patients with high risk of locoregional recurrence. RESULTS: Thirty-three patients were included. Among them, twelve received adjuvant lymph-node field radiotherapy. The median duration of follow-up was 17months (range: 8-45months). Patients receiving radiotherapy and immunotherapy had a significantly higher disease stage and more frequent extracapsular extension. At 12months, the disease-free survival rate was 66.7% for the patients receiving immunotherapy alone (95% CI: 42.5-82.5%) and 83.3% for those receiving radiotherapy and immunotherapy (95% CI: 48.2-95.6%; P=0.131). The locoregional progression rate was 24% in patients receiving immunotherapy and 8% in patients receiving immunotherapy and radiotherapy (P=0.379). After adjuvant treatment, 6% of patients developed grade 3 or above immunotherapy-related events and none developed grade 3 or above radiation-related adverse events. CONCLUSION: In patients with stage III melanoma, adjuvant lymph-node field radiotherapy combined with immunotherapy seems to be associated with longer disease-free survival, with acceptable tolerance. However, these results need to be confirmed by long-term and prospective studies.

Perioperative chemotherapy and immunotherapy to optimize cystectomy outcomes in the curative intent of non-metastatic muscle-invasive bladder cancer: A systematic review and meta-analysis.

INTRODUCTION: Perioperative systemic treatments play a crucial role in the comprehensive management of muscle-invasive bladder cancer. While neoadjuvant platinum-based chemotherapy has a proven efficacy, administering adjuvant chemotherapy can be challenging in patients with multiple comorbidities. Although immunotherapy has shown success in metastatic settings, its effectiveness in both neoadjuvant and adjuvant settings remains under investigation. This study aims to conduct a systematic literature review and meta-analysis to assess the impact of chemotherapy and/or immunotherapy in neoadjuvant and/or adjuvant settings. METHODS: A systematic review and meta-analysis were conducted by consulting the PubMed, Scopus, and ClinicalTrial.gov databases for the period from 1994 to 2023. The analysis utilized Forest Plots for key points of interest: overall survival/pathologic response for neoadjuvant chemotherapy (NAC) and overall survival/disease-free survival for adjuvant chemotherapy (AC), employing random or fixed models. RESULTS: The systematic review included 26 articles, and 14 were incorporated into the meta-analysis. For NAC, five studies assessed overall survival, yielding an overall hazard ratio (HR) of 0.84 [0.75-0.94]; P=0.002. Pathologic response under NAC was evaluated in five studies, resulting in an overall odds ratio (OR) of 0.3 [0.2-0.4]; P<0.001 compared to cystectomy and 0.86 [0.65-1.13]; P=0.28 for MVAC vs. GC. Regarding AC, six studies investigated overall survival, revealing an overall HR of 0.93 [0.77-1.12]; P=0.46. Disease-free survival under AC was examined in seven studies, with an overall OR of 0.58 [0.44-0.78]; P<0.001. Meta-analysis was not conducted for immunotherapy due to limited phase II studies in the neoadjuvant setting and only two available studies in the adjuvant setting. CONCLUSION: This study reaffirms the efficacy of platinum-based chemotherapy in neoadjuvant and adjuvant scenarios, enhancing overall survival in muscle-invasive bladder cancer patients. Immunotherapy exhibits promising outcomes in tumor downstaging in the neoadjuvant setting and in disease-free survival, in the adjuvant setting.

[First-line immunotherapy in non-small cell lung cancer diagnosed with brain metastases]. / CBNPC sans addictions oncogéniques métastatique cérébral d'emblée : place de l'immunothérapie.

INTRODUCTION: Up to 30% patients newly diagnosed with advanced non-small cell lung cancer (NSCLC) present with brain metastases. In the absence of oncogenic addiction, first-line immunotherapy, alone or in combination with chemotherapy, is the current standard of care. This review aims to synthesize the available data regarding the efficacy of immunotherapy in these patients, and to discuss the possibility of its being coordinated with local treatments such as radiotherapy. STATE OF THE ART: NSCLC patients with brain metastases appear to have survival benefits with immunotherapy similar to those of NSCLC patients without brain metastases. However, this finding is based on mainly prospective studies having included highly selected patients with pre-treated and stable brain metastases. Several retrospective studies and two prospective single-arm studies have confirmed the intracranial efficacy of immunotherapy, either alone or in combination with chemotherapy. PERSPECTIVES: The indications and optimal timing for cerebral radiotherapy remain subjects of debate. To date, there exists no randomized study assessing the addition of brain radiotherapy to first-line immunotherapy. That said, a recent meta-analysis showed increased intracerebral response when radiotherapy complemented immunotherapy. CONCLUSIONS: For NSCLC patients with brain metastases, the available data suggest a clear benefit of first-line immunotherapy, whether alone or combined with chemotherapy. However, most of these data are drawn from retrospective, non-randomized studies with small sample sizes.

[Atypical alveolar echinococcosis with systemic involvement in a patient treated with dupilumab]. / Une échinococcose alvéolaire atypique d'évolution systémique chez une patiente traitée par dupilumab.

INTRODUCTION: Alveolar echinococcosis is an endemic parasitic disease prevalent in certain cold regions of the Northern Hemisphere, including Eastern France, Switzerland, Germany, Canada, and the United States. Widely underdiagnosed, it is associated with infection by Echinococcus multilocularis, a small tapeworm belonging to the cestode class, capable of causing multi-systemic involvement, particularly in elderly or immunocompromised patients. CASE REPORT: We present the case of an 82-year-old patient, immunocompromised due to prolonged corticosteroid therapy and treatment with dupilumab. She was referred to our department for a diagnostic assessment of atypical hepatic and pulmonary lesions, initially suspected of tuberculosis or an IgG4-related disease. The hypothesis of alveolar echinococcosis caused by E. multilocularis was eventually considered based on a set of arguments, further confirmed by molecular diagnosis. We discuss the role of dupilumab in the systemic evolution and atypical presentation of the disease, through the induction of a specific immunosuppression. CONCLUSION: Alveolar echinococcosis should be systematically considered in case of systemic disease with prominent hepatic and pulmonary involvement, especially in immunocompromised patients.

[Surgical and pathological consequences of preoperative immunotherapy in onco-urology]. / Conséquences chirurgicales et anatomopathologiques de l'immunothérapie préopératoire en onco-urologie.

INTRODUCTION: Patients treated with immunotherapy might need surgical procedures in addition to the medical treatment. The main indications are cytoreductive nephrectomy, cystectomy (as part of clinical trials) and metastasis removal in some oligometastatic patients. This study aims to assess the feasibility of surgery for patients treated by immunotherapy and describes the histological modifications found in the pathological analysis. MATERIAL AND METHODS: We conducted a retrospective, monocentric study. We included all patients operated for a urologic cancer and previously treated with systemic immunotherapy between February 2018 and June 2022. We compared this population with a control group of patients treated with surgery without having previous immunotherapy. Patients were compared according to the cancer type, age and sex. We compared perioperative complications. We performed an analysis for evaluation of the peri-tumoral inflammatory infiltration. RESULTS: We included 50 patients in this study. The two groups were comparable in age (63.7 vs. 63.3years old, P=0.95) and sex (4 and 6 women in the first and second group). The peroperatory complication rate was comparable (20% vs. 16%, P=1). The mean bleeding volume was comparable (664 vs. 629mL; P=0.89). The postoperative complication rate (48% vs. 56%; P=0.78) and their grade (Clavien III-IV 8% vs. 24%; P=0.24) were comparable. The anatomopathological analysis described the same rate and intensity of peri-tumoral inflammatory infiltrate (96% vs. 96%; P=1). CONCLUSIONS: Preoperative immunotherapy does not appear to be associated with increased surgical difficulty and perioperative complications. Blind histological analysis of the surgical specimens did not reveal any specific features related to pre operative immunotherapy. LEVEL OF EVIDENCE: Grade 3 HAS.

[Cell therapy in all its forms]. / La thérapie cellulaire dans tous ses états.

Immunotherapy strategies have revolutionized the management of a significant number of patients in recent years, whether they are undergoing treatment for hematologic malignancies or solid tumors. This therapeutic class is extensive, ranging from antibodies targeting immune checkpoint molecules to adoptive cell therapy strategies, including bispecific antibodies and anticancer vaccines. All these strategies are currently in active development. Adoptive cell therapy involves the infusion of normal or genetically modified immune cells into a patient with the aim of restoring strong antitumor immunity, primarily associated with the cytotoxicity of T lymphocytes. Currently, there are three major adoptive cell therapy strategies: allogeneic hematopoietic stem cell transplantation, CAR-T cell therapy, and TCR-T cell therapy. The objective of this article is to describe the mechanisms of action of these three strategies as well as their current advantages, limitations and constraints.

[Place of innovative therapies in the management of cervical cancer]. / Place des thérapies innovantes dans la prise en charge des cancers du col de l'utérus.

Despite optimized screening and prevention strategies, cervical cancer remains a major public health problem, even in developed countries. In France, the incidence is estimated at 3159 cases per year in 2023. While the management of early-stage cases is now highly standardized, few therapeutic advances were made in the treatment of metastatic stages before 2021, before the therapeutic arsenal that we know today took off. The aim of this review is to summarize these advances.

[Combination of internal and external beam radiotherapy]. / Combinaison de la radiothérapie interne vectorisée et de la radiothérapie externe.

External beam radiation therapy and internal vectorized radiation therapy are two types of radiotherapy that can be used to treat cancer. They differ in the way they are administered, and the type of radiation used. Although they can be effective in treating cancer, they each have their own advantages and disadvantages, and their combination could be synergistic. Preclinical studies on combined internal and external beam radiation therapy have mainly used radiolabelled antibodies, whose bone marrow toxicity remains the limiting factor in increasing the administered activities. The use of small radioligands in clinical trials has shown to be better tolerated and more effective, which explains their rapid development. The results of preclinical studies on combined internal and external beam radiation therapy appear heterogeneous, making it impossible to determine an ideal therapeutic sequencing scheme, and complicating the transposition to clinical studies. The few clinical studies on combined internal and external beam radiation therapy available to date have demonstrated feasibility and tolerability. More work remains to be done in the fields of dosimetry and radiobiology, as well as in the sequencing of these two irradiation modalities to optimize their combination.