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1.
Gynecol Oncol ; 164(1): 231-241, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34716024

RESUMO

Human papillomaviruses (HPV)-related gynecological cancers are a major health care issue, and a leading cause of cancer death in low- and middle-income countries (LMIC). In 2020, the World Health Organization launched a program aimed at cervical cancer elimination, by screening and vaccination strategies. Offering the best possible care to women diagnosed with invasive cancer is a complementary objective. Treatment of cervical cancer as per modern standards is complex and multimodal, mainly relying on surgery, external-beam radiotherapy (+/-chemotherapy) and brachytherapy. In parallel with the pivotal role of multidisciplinary discussion, international societies provide guidance to define the most effective and least toxic anti-cancer strategy, homogenize treatment protocols and provide benchmark quality indicators as a basis for accreditation processes. The challenge is to offer the appropriate diagnostic workup and treatment upfront and to avoid non- evidence-based treatment that consumes resources, impairs quality of life (QoL), and compromises oncological outcome. Various strategies may be applied for improving treatment quality: development of surgical mentorship, companion-training programs and international cooperation. The lack of radiotherapy/brachytherapy facilities is a major concern in LMIC. Reinforcing international support in terms of education, training, research and development and technical cooperation with national projects is required to increase access to minimum requirements but also introduce modern techniques, upgrade radiotherapy/brachytherapy services, and expand access to modern systemic treatments. In countries with robust economies, compliance to standards should also be increased. Integrative cancer care and multidisciplinary approaches are needed to tackle the dual challenge of increasing cure rates while minimizing QoL impairment. Appropriate dimensioning of the resources to avoid harmful treatment delays and access to expert referral centers is also a priority.


Assuntos
Acessibilidade aos Serviços de Saúde , Infecções por Papillomavirus/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Braquiterapia , Feminino , Saúde Global , Humanos , Programas de Rastreamento , Papillomaviridae/imunologia , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/radioterapia , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/radioterapia , Vacinação
2.
Gynecol Oncol ; 157(3): 644-648, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32173045

RESUMO

INTRODUCTION: Since dose escalation allowed by image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer (LACC), local relapses have become a rare event. Only scarce data are available on the outcome of patients experiencing a local relapse after IGABT. METHODS: Between 2004 and 2016, all consecutive patients treated at Gustave Roussy Institute for LACC and receiving concomitant chemoradiation and IGABT were analysed. Clinical and treatment-related prognostic factors for survival after local relapse were searched, in order to potentially identify patients requiring salvage treatment. RESULTS: Two hundred and fifty-nine patients were treated during this period. With a median follow-up of 4.1 years, 10.8% (n = 28) had a local relapse. Among these patients, 53.6% had synchronous lymph nodes or distant metastatic relapse and only 13 patients (5% of all patients) had isolated local relapse. After local relapse, median survival was 47 months and three patients were alive at last follow-up. Only three patients with local relapse could receive salvage surgery (10.7%). Metastases occurrence and pelvic wall involvement were the main contraindications (67.9%) for salvage surgery. Among the three patients treated with surgery, two are still alive at last follow-up without significant complication. Improved survival was observed among the two patients who could have surgery (p = .02). Local progression led to serious symptoms in 75% of patients. Only the time interval between brachytherapy and relapse (<1 year) was prognostic for 2-year overall survival (p = .005). CONCLUSION: Salvage surgery is feasible in a very low number of highly selected patients with local relapse following IGABT. Local failure is a major cause of severe local symptoms, confirming that every effort should be done to achieve long-term local control through dose escalation.


Assuntos
Braquiterapia/métodos , Quimiorradioterapia/métodos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias do Colo do Útero/diagnóstico por imagem , Adulto Jovem
3.
Ann Oncol ; 28(6): 1191-1206, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28168275

RESUMO

Medical image processing and analysis (also known as Radiomics) is a rapidly growing discipline that maps digital medical images into quantitative data, with the end goal of generating imaging biomarkers as decision support tools for clinical practice. The use of imaging data from routine clinical work-up has tremendous potential in improving cancer care by heightening understanding of tumor biology and aiding in the implementation of precision medicine. As a noninvasive method of assessing the tumor and its microenvironment in their entirety, radiomics allows the evaluation and monitoring of tumor characteristics such as temporal and spatial heterogeneity. One can observe a rapid increase in the number of computational medical imaging publications-milestones that have highlighted the utility of imaging biomarkers in oncology. Nevertheless, the use of radiomics as clinical biomarkers still necessitates amelioration and standardization in order to achieve routine clinical adoption. This Review addresses the critical issues to ensure the proper development of radiomics as a biomarker and facilitate its implementation in clinical practice.


Assuntos
Diagnóstico por Imagem/métodos , Neoplasias/diagnóstico por imagem , Medicina de Precisão , Humanos , Processamento de Imagem Assistida por Computador/métodos , Oncologia
4.
Ann Oncol ; 28(11): 2691-2697, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29045516

RESUMO

BACKGROUND: Phase III randomized controlled trials (RCTs) are the cornerstone of evidence-based oncology. However, there is no exhaustive review describing the radiotherapy RTCs characteristics. The objective of the present study was to describe features of all phase III RCTs including at least a radiation therapy. METHODS AND MATERIALS: Requests were performed in the Medline database (via PubMed). The latest update was performed in April 2016, using the following MESH terms: 'clinical trials: phase III as topic', 'radiotherapy', 'brachytherapy', as keywords. RESULTS: A total of 454 phase III RCTs were identified. Studies were mainly based on open (92.1%) multicenter (77.5%) designs, analyzed in intend to treat (67.6%), aiming at proving superiority (91.6%) through overall survival assessment (46.5%). Most frequently studied malignancies were head and neck (21.8%), lung (14.3%) and prostate cancers (9.9%). Patients were mainly recruited with a locally advanced disease (73.7%). Median age was 59 years old. Out of 977 treatment arms, 889 arms experienced radiotherapy, mainly using 3D-conformal radiotherapy (288 arms, 32.4%). Intensity-modulated techniques were tested in 12 arms (1.3%). The intervention was a non-cytotoxic agent addition in 89 studies (19.6%), a radiation dose/fractionation modification in 74 studies (16.3%), a modification of chemotherapy regimen in 63 studies (13.9%), a chemotherapy addition in 63 studies (13.9%) and a radiotherapy addition in 53 trials (11.7%). With a median follow-up of 50 months, acute all-grade and grade 3-5 toxicities were reported in 49.6% and 69.4% of studies, respectively. Radiotherapy technique, follow-up and late toxicities were reported in 60.1%, 74%, and 31.1% of studies, respectively. CONCLUSION: Phase III randomized controlled trials featured severe limitations, since a third did not report radiotherapy technique, follow-up or late toxicities. The fast-paced technological evolution creates a discrepancy between literature and radiotherapy techniques performed in daily-routine, suggesting that phase III methodology needs to be reinvented.


Assuntos
Braquiterapia , Ensaios Clínicos Fase III como Assunto , Medicina Baseada em Evidências , Neoplasias/radioterapia , Conduta Expectante , Fracionamento da Dose de Radiação , Humanos , Prognóstico , Radioterapia Conformacional
6.
Ann Oncol ; 26(6): 1223-1229, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25701455

RESUMO

BACKGROUND: This phase I study evaluated the safety and efficacy of the oral mTOR inhibitor everolimus in combination with thoracic radiotherapy followed by consolidation chemotherapy in locally advanced or oligometastatic untreated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Everolimus dose was escalated in incremental steps [sequential cohorts of three patients until the occurrence of dose-limiting toxicity (DLT)] and administered orally weekly (weekly group: dose of 10, 20 or 50 mg) or daily (daily group: 2.5, 5 or 10 mg), 1 week before, and during radiotherapy until 3.5 weeks after the end of radiotherapy. Two cycles of chemotherapy (cisplatin-navelbine) were administrated 4.5 weeks after the end of radiotherapy. RESULTS: Twenty-six patients were included in two centers, 56% had adenocarcinoma and 84% had stage III disease. In the weekly group (12 assessable patients), everolimus could be administered safely up to the maximum planned weekly dose of 50 mg; however, one patient experienced a DLT of interstitial pneumonitis at the weekly dose level of 20 mg. In the daily group (9 assessable patients): one DLT of interstitial pneumonitis with a fatal outcome was observed at the daily dose level of 2.5 mg; two other DLTs (one grade 3 esophagitis and one bilateral interstitial pneumonitis) were found at the daily dose level of 5 mg. Overall there were five patients with G3-4 interstitial pneumonitis related to treatment. Among 22 assessable patients for response, there were 9 (41%) partial response and 7 (32%) stable disease. At a median follow-up of 29 months, the 2-year overall survival and progression-free survival actuarial rates were 31% and 12%, respectively. CONCLUSION: In previously untreated and unselected NSCLC patients, the recommended phase II dose of everolimus in combination with thoracic radiotherapy is 50 mg/week. Pulmonary toxicity is of concern and should be carefully monitored to establish the potential role of mTOR inhibitor with concomitant radiotherapy. EUDRACT N: 2007-001698-27.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia/métodos , Everolimo/administração & dosagem , Neoplasias Pulmonares/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Radioterapia Conformacional , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/mortalidade , Cisplatino/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Everolimo/efeitos adversos , Feminino , França , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/efeitos adversos , Dosagem Radioterapêutica , Radioterapia Conformacional/efeitos adversos , Radioterapia Conformacional/mortalidade , Fatores de Risco , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina
8.
Artigo em Inglês | MEDLINE | ID: mdl-38971686

RESUMO

AIMS: FAST-Forward and UK-FAST-trials have demonstrated the safety and efficacy of five-fraction breast adjuvant radiation therapy (RT) and have become the standard of care for selected early breast cancer patients. In response to the additional burden caused by the COVID-19 pandemic, we implemented "One-Week Breast RT," an innovative program delivering five-fraction whole breast RT in a complete 5-day workflow. The primary objective of this study was to demonstrate the feasibility and safety of our program. The secondary objective was to evaluate cosmetic results. MATERIAL AND METHODS: A total of 120 patients treated from February 2021 to March 2022, received whole breast RT without lymph node irradiation nor boost, with 26 Gy in five fractions over one week. Inverse planning with restricted optimization parameters offers systematic deep inspiration breath-hold aimed to provide treatment plans compliant with FAST-Forward recommendations. Toxicity and cosmetic evaluations were prospectively registered prior (pre-RT), at the end (end-RT), and 6 months after RT (6 months) based on Common Terminology Criteria for Adverse Events v. 4.03 and Harvard scale. RESULTS: With a median age of 70 years (interquartile range (IQR): 66-74) and a median follow-up of 6 months (IQR: 6.01-6.25), most patients (93.3%) completed their RT in one week from baseline to the end of the treatment consultation. The most common acute toxicities (at end-RT) were skin-related: radio-dermatitis (72%), induration (35%), hyperpigmentation (8%), and breast edema (16%). The rate of radio-dermatitis decreased from end-RT to 6 months (71.7% vs 5.4%, P< 0.001). No patient experienced grade ≥3 toxicity. At 6 months, cosmetic results were generally good or excellent (94.1%). CONCLUSION: This study confirms the feasibility and acute safety of the "One-Week Breast RT" in real life. Favorable toxicity profiles and good cosmetic outcomes are in line with FAST-Forward results. A prospective national cohort, aimed at decreasing treatment burden, maintaining safety, efficacy, and improving RT workflow efficiency with longer follow-up is ongoing.

9.
Ann Oncol ; 24(1): 38-46, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22898033

RESUMO

Novel irradiation techniques and radiosensitizing strategies revealed their interest for improving the antitumor efficacy of radiation therapy (RT) and thus for reducing locoregional failures. We analyzed the relevance of these strategies with regard to their impact on survival. The examples of the targeted molecular agent cetuximab and dose intensification in head and neck and lung cancer show that this benefit in local control is associated with a survival benefit. Large meta-analyses comparing sequential versus concurrent chemoradiation have also highlighted that improvement in local control is a major contributor to the survival benefit observed in chemoradiation trials. This close link between local control and survival encourages us to pursue our efforts to further improve the efficacy of RT. In some cases, the survival benefit afforded by radiotherapy is however marginal. The better understanding of the impact of local control on overall survival might allow optimization of clinical trials designs.


Assuntos
Neoplasias/radioterapia , Análise de Sobrevida , Antineoplásicos/uso terapêutico , Terapia Combinada , Relação Dose-Resposta à Radiação , Medicina Baseada em Evidências , Humanos , Neoplasias/tratamento farmacológico
10.
Ann Oncol ; 24(11): 2834-8, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24026540

RESUMO

BACKGROUND: The ACCORD 16 phase II trial aimed to evaluate the objective response rate after combination of conventional chemoradiotherapy (CRT) and cetuximab in locally advanced anal canal carcinoma (LAACC). PATIENTS AND METHODS: Immunocompetent patients with histologically confirmed LAACC received CRT [45 gray (Gy)] in 25 fractions over 5 weeks, fluorouracil and cisplatin during weeks 1 and 5), in combination with weekly dose of cetuximab (250 mg/m(2) with a loading dose of 400 mg/m(2) 1 week before irradiation), and a standard dose boost (20 Gy). The trial was originally designed to include 81 patients to detect a 15% of objective response increase with the new combination in comparison with CRT. RESULTS: The trial was prematurely stopped after the declaration of 15 serious adverse events (SAEs) in 14 out of 16 patients. Five patients received the entire planned treatment, and the compliance was higher after amendments of the protocol. Among the 15 SAEs, 6 were unexpected. Grade (G) 3/4 acute toxic effects, observed in 88% patients, were general (n = 13, 81%), digestive (n = 9, 56%), dermatological (n = 5, 31%), infectious (n = 4, 25%), haematological (n = 3, 19%), and others (n = 9); and three patients suffered from six G3/4 late toxic effects. No treatment-related death was reported. All 11 assessable patients had an objective response consisting of six complete (55%) and five partial (45%) response 2 months after the end of the treatment. Thirteen patients were followed up with a median of 22 months [95% confidence interval (CI ): 18-27] and had a 1-year colostomy-free survival, progression-free and overall survival rate of 67% (95% CI: 40%-86%), 62% (95% CI: 36%-82%), and 92% (95% CI: 67%-99%), respectively. CONCLUSION: CRT plus cetuximab was unacceptably toxic in this population of patients. Results of others phase II trials evaluating this combination are awaited to confirm these findings. EUDRA CT NO: 2007-007029-38.


Assuntos
Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/radioterapia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias do Ânus/patologia , Cetuximab , Quimiorradioterapia/efeitos adversos , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Radioterapia/efeitos adversos
11.
Invest New Drugs ; 31(6): 1530-8, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24077982

RESUMO

BACKGROUND: The kinesin spindle protein Eg5 is involved in mitosis, and its inhibition promotes mitotic arrest. EMD 534085, a potent, reversible Eg5 inhibitor, demonstrated significant preclinical antitumor activity. METHODS: This first-in-man, single-center, open-label, phase I dose-escalation study (3 + 3 design) investigated EMD 534085 safety, pharmacokinetics and antitumor activity in refractory solid tumors, Hodgkin's lymphoma, or non-Hodgkin's lymphoma. EMD 534085 (starting dose 2 mg/m²/day) was administered intravenously every 3 weeks. Doses were escalated in 100% steps in successive cohorts of 3 patients until grade 2 toxicity occurred, followed by 50% until the first dose-limiting toxicity (DLT) arose. If <2 of 6 patients experienced a DLT, doses were further increased by 25%. Dose-escalation was stopped if a DLT occurred in ≥2 of 6 patients. RESULTS: Forty-four patients received EMD 534085. Median treatment duration was 43 days (range, 21-337). Thirty-eight patients (86%) received ≥2 cycles. DLTs were grade 4 neutropenia (1 patient each at 108 and 135 mg/m²/day), and grade 3 acute coronary syndrome with troponin I elevation (1 patient at 135 mg/m²/day). The maximum tolerated dose (MTD) was 108 mg/m²/day. The most common treatment-related adverse events were asthenia (50%) and neutropenia (32%). EMD 534085 appeared to have linear pharmacokinetics. Increase in phospho-histone H3 positive cells in paired pre- and on-treatment biopsies showed evidence of target modulation. No complete or partial responses were observed. Best response was stable disease in 23 patients (52%). CONCLUSIONS: EMD 534085 appeared to be well tolerated; MTD was 108 mg/m²/day. Preliminary antitumor results suggested limited activity in monotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Cinesinas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Quinolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/patologia , Quinolinas/sangue , Quinolinas/farmacocinética , Carga Tumoral/efeitos dos fármacos
12.
Cancer Radiother ; 27(6-7): 491-493, 2023 Sep.
Artigo em Francês | MEDLINE | ID: mdl-37596124

RESUMO

Radiation-induced pulmonary fibrosis (RIPF) is one of the major and late complications of radiotherapy (RT) with an average incidence rate between 16 and 28% after RT. RIPF significantly affects the function of the affected tissues/organs as well as the quality of life and survival of patients. The process of radiation fibrogenesis is initiated by a very complex signaling network that involves several cellular and molecular factors and the development of effective treatments relies on a better understanding of the involved mechanisms. Despite a major advance in the field, to date there is no clinical treatment that has really shown efficacy in the prevention or treatment of RIPF. In the present review, we will discuss potential new therapeutic avenues that could effectively treat RIPF.


Assuntos
Fibrose Pulmonar , Radioterapia (Especialidade) , Humanos , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/prevenção & controle , Qualidade de Vida , Transdução de Sinais
13.
Cancer Radiother ; 27(6-7): 511-518, 2023 Sep.
Artigo em Francês | MEDLINE | ID: mdl-37661506

RESUMO

Taking the immune system into account in the fight against tumors has upset the cancer treatment paradigm in the 21st century. Combination treatment strategies associating radiotherapy with immunotherapy are being increasingly implemented in clinical practice. In this context, lymphocytes, whether lymphocytes infiltrating the tumour, circulating blood lymphocytes or lymphocytes residing within the lymph nodes, are key players in cellular and humoral anti-tumor immunity. The significant radiosensitivity of lymphocytes was demonstrated in the early 1990s. Along with the cells of the digestive mucosa, lymphocytes are thus among the most radiosensitive cell types in the body. Compared to the old practices of external radiotherapy, current intensity modulated treatments have allowed a considerable improvement in acute and late toxicity, at the cost of a significant increase in the volume irradiated at low doses. This is not without consequence on the incidence of radiation-induced lymphopenia, with prognostic implications for many tumor types. Thus, in order not to hinder the action of antitumor immunity and the efficacy of immunotherapy, it is essential to consider lymphocytes as a new organ at risk in its own right. In this development, based on current data from the literature, we will begin by justifying the necessary prevention of radiation-induced lymphopenia, before providing the tools currently known to apprehend lymphocytes as a new multicompartments. Finally, we will broaden the perspective by outlining ways to develop research in this area.


Assuntos
Linfócitos , Linfopenia , Neoplasias , Lesões por Radiação , Radioterapia , Linfopenia/etiologia , Linfopenia/prevenção & controle , Lesões por Radiação/complicações , Linfócitos/efeitos da radiação , Neoplasias/radioterapia , Humanos , Radioterapia/efeitos adversos
14.
Cancer Radiother ; 27(6-7): 643-647, 2023 Sep.
Artigo em Francês | MEDLINE | ID: mdl-37516639

RESUMO

Radiation-induced toxicity of the digestive tract is a major clinical concern as many cancer survivors have received radiotherapy for tumours of the abdominopelvic area. The coordination and orchestration of a tissue's response to stress depend not only on the phenotype of the cells that make up the tissue but also on cell-cell interactions. The digestive system, i.e., the intestine/colon/rectum, is made up of a range of different cell populations: epithelial cells, stromal cells, i.e. endothelial cells and mesenchymal lineages, immune cells and nerve cells. Moreover, each of these populations is heterogeneous and presents very significant plasticity and differentiation states. The pathogenesis of radiation-induced digestive lesions is an integrated process that involves multiple cellular compartments interacting in a complex sequence of events. Understanding all the cellular events and communication networks that contribute to the tissue's response to stress is therefore a major conceptual and methodological scientific challenge. The study of heterogeneous populations of cells in a tissue is now possible thanks to "single cell' RNA sequencing and spatial transcriptomics techniques, which enable a comprehensive study of the transcriptomic profiles of individual cells in an integrated system. In addition, the mathematical and bioinformatics tools that are now available for the large-scale analysis of data allow the inference of cell-cell communication networks. Such approaches have become possible through advances in bioinformatics algorithms for the analysis and deciphering of interaction networks. Interactions influence the tissue regeneration process through expression of various molecules, including metabolites, integrins, junction proteins, ligands, receptors and proteins secreted into the extracellular space. The vascular network is viewed as a key player in the progression of digestive lesions, which are characterised by infiltration of a range of immune cells. A better characterisation of endothelium/immune cell interactions in suitable preclinical models, as well as in humans, may help to identify some promising therapeutic targets for the prediction, prevention or treatment of digestive toxicity after radiotherapy.


Assuntos
Neoplasias , Lesões por Radiação , Humanos , Células Endoteliais , Endotélio Vascular/patologia , Neoplasias/patologia , Lesões por Radiação/patologia , Fenótipo
15.
Br J Cancer ; 107(2): 308-14, 2012 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-22691970

RESUMO

BACKGROUND: Combined-modality therapy is a promising approach to improve the therapeutic index of radiotherapy. However, these improvements could come at the cost of increased toxicities. Clinical trials evaluating anti-tumour efficacy of bevacizumab combined with radiotherapy have encountered unexpected side effects. This study is the first systematic evaluation of normal tissue toxicity triggered by anti-angiogenic agents combined with radiation therapy in mice. METHODS: Effect of a mouse anti-VEGF antibody was monitored on acute toxicity studying radiation-induced intestinal ulceration (12 Gy TBI); on subacute toxicity using a model of oral mucositis (16.5 Gy); on late radiation injuries by monitoring lung fibrosis (bleomycin and 19 Gy). RESULTS: Combination of irradiation with anti-VEGF antibody enhanced intestinal damages with severe epithelial ulcerations, had no adverse impact on oral mucositis and dramatically worsened the fibrotic picture induced by bleomycin and irradiation to the lung. INTERPRETATION: These reports bring to light the important questions about safety and underscore the need for appropriate preclinical modelling of the impact on normal tissues of novel drug-radiation regimens. Our findings also highlight the complexity of anti-VEGF action, which could in defined conditions exert tissue-specific protection. The findings indicate that the combination of targeted drugs with radiotherapy should be approached with caution.


Assuntos
Inibidores da Angiogênese/toxicidade , Lesões Experimentais por Radiação/etiologia , Radioterapia/efeitos adversos , Animais , Bleomicina/toxicidade , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Feminino , Fibrose/etiologia , Intestinos/efeitos da radiação , Pulmão/patologia , Pulmão/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Bucal/patologia , Mucosa Bucal/efeitos da radiação , Dosagem Radioterapêutica , Estomatite/etiologia
16.
Ann Oncol ; 23(5): 1301-1306, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21917737

RESUMO

BACKGROUND: Sequential tumour biopsies are of potential interest for the rational development of molecular targeted therapies. PATIENTS AND METHODS: From June 2004 to July 2009, 186 patients participated in 14 phase I clinical trials in which sequential tumour biopsies (13 trials) and/or sequential normal skin biopsies (6 trials) were optional. All patients had to sign an independent informed consent for the biopsies. RESULTS: Tumour biopsies were proposed to 155 patients and 130 (84%) signed the consent while normal skin biopsies were proposed to 70 patients and 57 (81%) signed the consent. Tumour biopsies could not be carried out in 41 (31%) of the 130 consenting patients. Tumour biopsies were collected at baseline in 33 patients, at baseline and under treatment in 56 patients. Tumour biopsies were obtained using an 18-gauge needle, under ultrasound or computed tomography guidance. Only nine minor complications were recorded. Most tumour biopsy samples collected were intended for ancillary molecular studies including protein or gene expression analysis, comparative genomic hybridization array or DNA sequencing. According to the results available, 70% of the biopsy samples met the quality criteria of each study and were suitable for ancillary studies. CONCLUSIONS: In our experience, the majority of the patients accepted skin biopsies as well as tumour biopsies. Sequential tumour and skin biopsies are feasible and safe during early-phase clinical trials, even when patients are exposed to anti-angiogenic agents. The real scientific value of such biopsies for dose selection in phase I trials has yet to be established.


Assuntos
Pesquisa Biomédica/métodos , Ensaios Clínicos Fase I como Assunto/efeitos adversos , Ensaios Clínicos Fase I como Assunto/métodos , Neoplasias/patologia , Aceitação pelo Paciente de Cuidados de Saúde , Pele/patologia , Adolescente , Adulto , Idoso , Algoritmos , Biópsia/efeitos adversos , Biópsia/métodos , Biópsia/psicologia , Biópsia/estatística & dados numéricos , Ensaios Clínicos Fase I como Assunto/psicologia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Segurança do Paciente/estatística & dados numéricos , Adulto Jovem
17.
Invest New Drugs ; 30(6): 2318-26, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22215532

RESUMO

BACKGROUND: ES-285 (spisulosine) is a novel compound derived from the marine mollusk Spisula polynoma with evidence of preclinical antitumor activity. This phase I clinical trial was designed to identify the maximum tolerated dose (MTD) and the recommended dose for phase II trials (RD), as well as to evaluate the safety profile, pharmacokinetics and preliminary efficacy data of ES-285 in patients with advanced solid tumors. PATIENTS AND METHODS: Sixty-one patients at two medical institutions were treated with a 3-h ES-285 intravenous infusion every 3 weeks. Nine dose levels were evaluated. RESULTS: No dose-limiting toxicities (DLTs) were observed during dose escalation from 4 to 128 mg/m(2). Six patients had seven DLTs at the three highest dose levels tested: 256 mg/m(2) (n = 2), 200 mg/m(2) (n = 3) and 160 mg/m(2) (n = 1). Grade 3/4 transaminase increases (n = 3), grade 3/4 central nervous system disorders [confusion (n = 2) and ataxia (n = 1)], and grade 3 pyrexia (n = 1) were the dose-limiting toxicities found with this ES-285 administration schedule. Pharmacokinetic analysis showed ES-285 dose linearity, wide distribution and a long half-life. One non-confirmed partial response was observed in a patient with metastatic melanoma treated with ES-285 128 mg/m(2), and 18 patients showed stable disease at different dose levels, lasting longer than 3 months in six patients. CONCLUSION: Dose level VIII (200 mg/m(2)) was considered the MTD, and dose level IX (160 mg/m(2)) was defined as the RD. Limited antitumor activity was observed.


Assuntos
Antineoplásicos/administração & dosagem , Lipídeos/administração & dosagem , Adulto , Idoso , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Lipídeos/sangue , Lipídeos/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
18.
Cancer Radiother ; 26(6-7): 955-961, 2022 Oct.
Artigo em Francês | MEDLINE | ID: mdl-36030189

RESUMO

Thanks to the success of checkpoint inhibitors, immunotherapy now plays a major role in the management of a large number of solid tumors, while the number of indications continues to grow and new combinations could, in the near future, further modify treatment standards. However, the response rates of immunotherapies as monotherapy are modest and their use is increasingly considered in combination with other cancer treatments (chemotherapy, surgery, radiotherapy or certain targeted therapies). Combinations with radiotherapy seem particularly attractive because there is a strong experimental rationale linking part of the efficacy of ionizing radiation to an induced stimulation of both of the innate and adaptive response. Many early phases and a number of large randomized combination trials have published efficacy and safety results, while important trials are still ongoing and will provide answers in the near future. This short review recalls the experimental biological rationale for immuno-radiotherapy and highlights some of the fundamental directions being explored, then presents the clinical efficacy and safety results available to date, those expected in the near future, and finally outlines the outlook in this rapidly evolving field.


Assuntos
Neoplasias , Radioterapia (Especialidade) , Humanos , Imunoterapia/métodos , Neoplasias/radioterapia
19.
Cancer Radiother ; 26(1-2): 96-103, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34953704

RESUMO

The place of personalized treatments is highly increasing in medical and radiation oncology. During the last decades, a huge number of assays have been developed to predict responses of normal tissues and tumours. These tests have not yet been included into daily clinical practice but the recent developments of radiation oncology are paving the way of personalized strategies including the risk of tumour recurrence and normal tissue reactions. Concerning tumor radiosensitivity prediction, no test are currently used, even if the radiosensitivity index and the genome-based model for adjusting radiotherapy dose assays seem the most promising with level II of evidence. Commercial developments are under progress. Concerning normal tissue radiosensitivity prediction, single nucleotide polymorphims of prostate cancer patients and radiation-induced CD8 T-lymphocyte apoptosis breast and prostate assays are of level I of evidence. They can be proposed before the beginning of radiotherapy in order to propose personalized treatments according to both risks of tumour and normal tissue radiosensitivity. Commercial developments are also under way.


Assuntos
Neoplasias/radioterapia , Órgãos em Risco/efeitos da radiação , Medicina de Precisão/métodos , Tolerância a Radiação/genética , Reparo do DNA , Fibroblastos/efeitos da radiação , Expressão Gênica , Marcadores Genéticos , Humanos , Neoplasias/genética , Neoplasias/imunologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Resultado do Tratamento
20.
ESMO Open ; 7(2): 100451, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35427841

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disrupted clinical practice, research and teaching. During peaks, virtual courses were implemented but these changes are poorly described, especially for oncology postgraduate students and faculty teachers. PATIENTS AND METHODS: We administered two surveys from June 2021 to October 2021 to students and faculty teachers (250 and 80 responses, respectively) who registered at Gustave Roussy School of Cancer Sciences (Université Paris-Saclay) during 3 consecutive university years (October 2018 to October 2021), where a major shift to e-learning was associated with COVID-19 pandemic. RESULTS: Most students were female (53%), attending physicians (50%), aged 30-39 years (54%) and 2020-2021 (66.4%) was the main year of training. Most faculty teachers were male (58%), aged 40-50 years (44%) and had participated in training for at least 3 years (83%). More than half of the students received 100% virtual training [55% versus 45% face-to-face/mixed teaching modalities; online (84%) versus remote teaching (16%)]. Only 34% of students declared >80% 'active listening' and only 16% of teachers considered e-learning to be more suitable (compared with face-to-face) for postgraduate education. Virtual teaching decreased student-teacher interactions as compared with mixed/face-to-face (lessons were sufficiently interactive for 54% students if virtual only teaching versus for 71% if other teaching modalities; P = 0.009). Teachers stated that virtual learning did not lead to any improvements in terms of attendance (68%), interaction (74%) and quality of teaching (68%). However, most faculty (76%) acknowledged that partial e-learning training should be maintained outside the pandemic, if it represents ≤50% of the whole teaching (teachers: 79% versus student: 66%; P = 0.04). CONCLUSIONS: COVID-19 accelerated the transition toward novel practices. Students and faculty teachers agreed on the need for future mixed (≤50% e-learning) teaching modalities. Adequate formation and the use of codified best newer virtual practices are required.


Assuntos
COVID-19 , Estudantes de Medicina , COVID-19/epidemiologia , Docentes , Feminino , Humanos , Masculino , Pandemias , SARS-CoV-2
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