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Venous thromboembolism (VTE) is a common and potentially life-threatening complication in patients with cancer. Both cancer and its treatments increase the risk of developing VTE. Specific cancer types and individual patient comorbidities increase the risk of developing cancer-associated VTE, and the risk of bleeding is increased with anticoagulation therapies. The aims of this article are to summarize the latest evidence for treating cancer-associated VTE, discuss the practical considerations involved, and share best practices for VTE treatment in patients with cancer. The article pays particular attention to challenging contexts including patients with brain, lung, gastrointestinal, and genitourinary tumors and those with hematological malignancies. Furthermore, the article summarizes specific clinical scenarios that require additional treatment considerations, including extremes of body weight, nausea and gastrointestinal disturbances, compromised renal function, and anemia, and touches upon the relevance of drug-drug interactions. Historically, vitamin K antagonists and low-molecular-weight heparins (LMWHs) have been used as therapy for cancer-associated VTE. The development of direct oral anticoagulants has provided additional treatment options, which, in certain instances, offer advantages over LMWHs. There are numerous factors that need to be considered when treating cancer-associated VTE, and although various treatment guidelines are helpful, they do not reflect each unique scenario that may arise in clinical practice. This article provides a summary of the latest evidence and a practical approach for treating cancer-associated VTE.
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In the original article [...].
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Senescência Celular , Resistencia a Medicamentos Antineoplásicos , Melanoma , Mutação , Fenótipo , Proteínas Proto-Oncogênicas B-raf , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Melanoma/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Senescência Celular/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismoRESUMO
OBJECTIVES: External beam radiation with sensitizing platinum is the recommended therapy for locally advanced vulvar cancers not amenable to curative surgery and is associated with considerable acute and chronic side effects. Radical vulvectomy post-radiation for persistent disease is often compromised with poor wound healing. We describe clinical outcomes for patients who received neoadjuvant chemotherapy plus bevacizumab followed by radical vulvectomy for locally advanced vulvar cancer. METHODS: We performed retrospective analyses of all patients at our institution who underwent radical vulvectomy from January 2015 to November 2023. Of 113 patients, 13 patients underwent neoadjuvant chemotherapy. Demographics and clinicopathologic data were extracted, and descriptive statistical analyses were performed. Cases with neoadjuvant chemotherapy plus bevacizumab were further evaluated for response, adverse effects, and survival. RESULTS: Neoadjuvant chemotherapy was administered to 13 patients with stage II-IV disease that involved the urethra, vagina, or anus. Lesion sizes ranged from 4 to 20 cm (median 7 cm). Patients received 2-6 cycles of carboplatin or cisplatin, paclitaxel, and bevacizumab. Nine (69.2%) patients had partial pathologic responses, and four patients had complete responses. All patients had negative surgical margins. Ten (76.9%) patients had radiographic evidence of inguinal lymph node metastasis prior to neoadjuvant chemotherapy, and four had residual nodal disease. Only one patient developed a superficial groin seroma. Three patients developed recurrence, two locally and one distant, and there was one death. The median follow-up was 23 months (range 6-84 months). CONCLUSIONS: Neoadjuvant chemotherapy using combination platinum/paclitaxel/bevacizumab was efficacious for locally advanced vulvar cancer, resulting in complete resections, negative margins, and excellent wound healing. A multi-institutional phase II trial is warranted to validate these findings.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Terapia Neoadjuvante , Neoplasias Vulvares , Humanos , Feminino , Bevacizumab/administração & dosagem , Neoplasias Vulvares/tratamento farmacológico , Neoplasias Vulvares/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Paclitaxel/administração & dosagem , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Vulvectomia , Idoso de 80 Anos ou maisRESUMO
Forchlorfenuron (FCF) is a widely used plant cytokinin that enhances fruit quality and size in agriculture. It also serves as a crucial pharmacological tool for the inhibition of septins. However, the precise target of FCF has not yet been fully determined. This study reveals a novel target of FCF and elucidates its downstream signaling events. FCF significantly impairs mitochondrial respiration and mediates metabolic shift toward glycolysis, thus making cells more vulnerable to glycolysis inhibition. Interestingly, FCF's impact on mitochondrial function persists, even in cells lacking septins. Furthermore, the impaired mitochondrial function leads to the degradation of HIF-1α, facilitated by increased cellular oxygen. FCF also induces AMPK activation, suppresses Erk1/2 phosphorylation, and reduces the expression of HER2, ß-catenin, and PD-L1. Endometrial cancer is characterized by metabolic disorders such as diabetes and aberrant HER2/Ras-Erk1/2/ß-catenin signaling. Thus, FCF may hold promise as a potential therapeutic in endometrial cancer.
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INTRODUCTION: Currently three antibody-drug-conjugates (ADC) are approved by the European Medicines Agency (EMA) for treatment of breast cancer (BC) patient: trastuzumab-emtansine, trastuzumab-deruxtecan and sacituzumab-govitecan. ADC are composed of a monoclonal antibody (mAb) targeting a specific antigen, a cytotoxic payload and a linker. Pharmacokinetics (PK) and pharmacodynamics (PD) distinguish ADC from conventional chemotherapy and must be understood by clinicians. AREAS COVERED: Our review delineates the PK/PD profiles of ADC approved for the treatment of BC with insight for future development. This is an expert opinion literature review based on the EMA's Assessment Reports, enriched by a comprehensive literature search performed on Medline in August 2023. EXPERT OPINION: All three ADC distributions are described by a two-compartment structure: tissue and serum. Payload concentration peak is immediate but remains at low concentration. The distribution varied for all ADC only with body weight. mAb will be metabolised firstly by the saturable complex formation of ADC/Tumour-Receptor and secondly by binding of FcgRs in immune cells. They are all excreted in the bile and faeces with minimal urine elimination. Dose adjustments, apart from weight, are not recommended. Novel ADC are composed of cleavable linkers with various targets/payloads with the same PK/PD properties, but novel structures of ADC are in development.
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Antineoplásicos , Neoplasias da Mama , Imunoconjugados , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Trastuzumab , Ado-Trastuzumab Emtansina/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêuticoRESUMO
PURPOSE: We aimed to assess the impact of surgery of primary tumor in overall survival (OS) of women with de novo metastatic breast cancer. METHODS: Nationwide, population-based retrospective cohort study of women diagnosed with de novo metastatic breast cancer in Belgium, between Jan/2010-Dec/2014. Data was obtained from the Belgian Cancer Registry and administrative databases. "Surgery" group was defined by surgery of primary tumor up to nine months after diagnosis. We excluded women who did not receive systemic treatment or did not complete nine months follow-up after diagnosis. All the subsequent analyses reporting on overall survival and the stratified outcome analyses were performed based on this nine-month landmark cohort. OS was estimated using Kaplan-Meier method and compared using adjusted Cox proportional hazards models controlling for confounders with 95% confidence intervals (CI). We performed a stratified analysis according to surgery timing and a propensity score matching analysis. RESULTS: 1985 patients, 534 (26.9%) in the "Surgery" and 1451 (73.1%) in the "No Surgery" group. Patients undergoing surgery were younger (p < 0.001), had better performance status (PS) (p < 0.001), and higher proportion of HER2-positive and triple-negative breast cancer (p = 0.012). Median follow-up was 86.0 months (82.6-88.5). Median OS was 60.1 months (57.1-68.2) in the "Surgery" vs. 41.9 months (39.8-44.2) in the "No Surgery" group (adjusted HR 0.56; 0.49-0.64). OS was similar when surgery was performed upfront or after systemic treatment. Propensity score matching analysis confirmed the same findings. CONCLUSION: Among patients receiving systemic treatment for de novo metastatic breast cancer and surviving nine months or more, those who received surgery of the primary tumor within nine months of diagnosis have longer subsequent survival than those who did not.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/cirurgia , Neoplasias da Mama/diagnóstico , Prognóstico , Bélgica/epidemiologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
In the original article [...].
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BACKGROUND: Febrile neutropenia (FN) is a relatively common complication of cytotoxic chemotherapy. Prophylaxis with granulocyte colony-stimulating factor (G-CSF) can prevent FN and chemotherapy dose delays and enable the use of the higher dose intensities associated with a survival benefit; however, GCSF is not always used optimally. Five medical oncologists with a special interest in supportive care met to discuss the evidence for prophylaxis with GCSF to improve survival in cancer patients, identify reasons why this is not always done, and suggest potential solutions. The dose intensity of chemotherapy is critical for maximizing survival in cancer patients but may be reduced as a result of hematological toxicity, such as FN. Use of GCSF has been shown to increase the chances of achieving the planned dose intensity in various cancers, including early-stage breast cancer and non-Hodgkin lymphoma. All physicians treating cancer patients should consider the use of GCSF prophylaxis in patients receiving chemotherapy, paying particular attention to patient-related risk factors. KEY MESSAGES: Strategies to optimize GCSF use include educating medical oncologists and pharmacists on the appropriate use of GCSF and informing patients about the efficacy of GCSF and its potential adverse effects. It is hoped that the evidence and opinions presented will help to encourage appropriate use of GCSF to support cancer patients at risk of FN in achieving the best possible outcomes from chemotherapy.
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High-grade serous ovarian cancer (HGSOC) is a particularly lethal malignancy that is prognostically influenced by the immune profile of the tumor microenvironment (TME). TME immune profiles have been sub-categorized according to features associated with both survival outcomes as well as response to systemic therapies. Five suggested immune phenotypes have been described and correlated with overall survival outcomes. Phenotypes associated with shorter overall survival rates appear to have prominent immunosuppressive features within their TME. The opportunity to triage patients according to their prognostic TME profile might allow selection of individual patients with poor prognostic features who could most benefit from innovative immunomodulatory treatment strategies. Two potential strategies to indirectly manipulate the TME (and oncologic outcomes) are alteration of the gut microbiome composition and alteration of TME metabolism through dietary interventions. Experimental dietary modifications in humans designed for influencing cancer outcomes are only beginning to be studied in a prospective fashion. Herein we summarize prognostic TME features in HGSOC and potential opportunities for immunomodulation via dietary and gut microbial interventions.
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Neoplasias Ovarianas , Microambiente Tumoral , Humanos , Feminino , Prognóstico , Imunomodulação , Imunidade , Neoplasias Ovarianas/patologiaRESUMO
PURPOSE OF REVIEW: Incidence of brain metastases increases overtime therefore it is important to rapidly progress in the discovery of new strategies of treatment for these patients. In consequence, more and more preclinical models of brain metastases (BM) are established to study new treatments for melanoma, lung, and breast cancer BM. Here, we reviewed the most recent findings of new drugs assessed in BM mouse preclinical models. RECENT FINDINGS: BM are a common metastatic site of several types of solid cancers and can be difficult to treat due to the unique environment of the brain and the blood-brain barrier. Currently, several preclinical models of BM have been demonstrated that new molecular targeted therapies, small metabolic inhibitors, immunotherapies or a combination of these drugs with radiotherapy lead to a reduction of BM growth and an improvement of mouse survival. SUMMARY: The use of preclinical models of BM is crucial to discover new treatment strategies for patients with BM. In the last years, some new drugs have been highlighted in preclinical models and are now tested in clinical trials including patients with brain metastases.
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Neoplasias Encefálicas , Melanoma , Animais , Camundongos , Biologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Melanoma/tratamento farmacológico , Neoplasias PulmonaresRESUMO
Second-line treatment of endometrial cancer is an unmet medical need. Lurbinectedin showed promising antitumor activity in a phase I study in combination with doxorubicin in advanced endometrial cancer. This phase 2 Basket trial evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 73 patients with pretreated endometrial cancer. The primary endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and an exploratory translational study. Confirmed complete (CR) and partial response (PR) was reported in two and six patients, respectively (ORR = 11.3%; 95%CI, 5.0-21.0%). Median DoR was 9.2 months (95%CI, 3.4-18.0 months), median PFS was 2.6 months (95%CI, 1.4-4.0 months) and median OS was 9.3 months (95%CI, 6.1-12.8 months). Molecular subtypes showed differences in PFS rate at 6 months (p53abn 23.7% vs. "No Specific Molecular Profile" [NSMP] 42.9%) and median OS (p53abn 6.6 months vs. NSMP 16.1 months). The most common treatment-related adverse events (mostly grade 1/2) were fatigue (54.8% of patients), nausea (50.7%), vomiting (26.0%) decreased appetite (17.8%). and constipation, (19.2%). The most common grade 3/4 toxicity was neutropenia (43.8%; grade 4, 19.2%; febrile neutropenia, 4.1%). In conclusion, considering the exploratory aim of this trial and the hints of antitumor activity observed together with a predictable and manageable safety profile, further biomarker-based development of lurbinectedin is recommended in this indication in combination with other agents. Clinicaltrials.gov identifier: NCT02454972.
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Neoplasias do Endométrio , Neutropenia , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carbolinas/efeitos adversos , Doxorrubicina/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Neutropenia/induzido quimicamenteRESUMO
BACKGROUND: Bromodomain and extraterminal domain (BET) inhibitors have demonstrated efficacy in solid tumours and haematological malignancies. BI 894999 is a novel oral BET inhibitor that has demonstrated potent antitumour activity in preclinical studies. PATIENTS AND METHODS: 1367.1 was an open-label, Phase Ia/Ib dose-finding study evaluating BI 894999 once daily in patients with advanced solid tumours (Schedule A: 0.2, 0.5, 1.0, 1.5, 2.0, and 5.0â¯mg, Days 1-21/21-d cycle; Schedule B: 1.5, 2.0, and 2.5â¯mg, Days 1-15/21-d cycle; Schedule C: loading dose 5.0, 6.0, or 7.0â¯mg on Day 1 followed by maintenance dose 2.5, 3.0, or 3.5â¯mg, Days 2-7 and 15-21/28-d cycle); 77 patients were enrolled. NCT02516553. RESULTS: Grade ≥3 dose-limiting toxicities (DLTs) were reported in 8/21, 5/25, and 9/31 patients for Schedules A, B, and C, respectively. Thrombocytopenia was reported as a DLT in 28.6%, 4.8%, and 9.7% for Schedules A, B, and C, respectively. Other DLTs occurring in ≥1 patient were troponin T increase (13.6%), hypophosphataemia (4.5%), and elevated creatine phosphokinase (3.0%). Disease control was achieved in 23.8%, 24.0%, and 29.0% of patients for Schedules A, B, and C, respectively. A partial response was achieved in 9.5% and 4% of patients with Schedules A and B, respectively. The best response with Schedule C was stable disease. CONCLUSION: The 1.5, 2.5, and 6.0/3.0â¯mg doses in Schedules A, B, and C, respectively, were declared as maximum tolerated dose. Based on the strength of these data, BI 894999 was further evaluated in a Phase Ib trial.
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Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Derivados de Benzeno , Dose Máxima Tolerável , Relação Dose-Resposta a DrogaRESUMO
Antibody-drug conjugates (ADCs) are a class of antineoplastic agents whose structure is composed of three main components: a monoclonal antibody (mAB) targeting a specific target antigen, a cytotoxic payload, and a linker binding the antibody to the payload. By combining the specificity of mABs with the high potency of the payloads, ADCs constitute a smart drug delivery system with improved therapeutic index. After recognition and binding of the mAB to its target surface antigen, ADCs are internalized by endocytosis by the tumor cell, releasing the payloads into the cytoplasm, where they exert their cytotoxic activity, eventually leading to cell death. The composition of some of the new ADCs confers additional functional properties that allow expanding their activity to neighboring cells not expressing the target antigen, constituting a valuable strategy to overcome tumor heterogeneity. Some of these 'off-target effects', such as the bystander effect, are possibly the mechanism underlying the antitumor activity demonstrated in patients with low expression of the target antigens, which represents an important paradigm shift in anticancer targeted therapy. Three ADCs are currently approved for the treatment of breast cancer (BC); two anti-HER2 (human epidermal growth factor receptor 2) ADCs (trastuzumab emtansine and trastuzumab deruxtecan); and one Trop-2-targeted ADC (sacituzumab govitecan). Based on the unprecedented efficacy data demonstrated by these agents, ADCs have been incorporated as part of standard regimens for all subtypes of advanced BC, as well as for high-risk early HER2-positive BC. Despite the remarkable advances, several hurdles still remain to overcome, including the development of reliable biomarkers for patient selection, prevention, and management of potentially severe toxicities, ADC resistance mechanisms, post-ADC resistance patterns, and optimal treatment sequencing and combinations. In this review, we will summarize the currently available evidence related to the use of these agents, as well as explore the current landscape of ADC development for BC treatment.
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Despite important advances in the treatment of metastatic melanoma with the development of MAPK-targeted agents and immune checkpoint inhibitors, the majority of patients either do not respond to therapies or develop acquired resistance. Furthermore, there is no effective targeted therapy currently available for BRAF wild-type melanomas (approximately 50% of cutaneous melanoma). Thus, there is a compelling need for new efficient targeted therapies. Prohibitins (PHBs) are overexpressed in several types of cancers and implicated in the regulation of signaling networks that promote cell invasion and resistance to cell apoptosis. Herein, we show that PHBs are highly expressed in melanoma and are associated with not only poor survival but also with resistance to BRAFi/MEKi. We designed and identified novel specific PHB inhibitors that can inhibit melanoma cell growth in 3D spheroid models and a large panel of representative cell lines with different molecular subtypes, including those with intrinsic and acquired resistance to MAPKi, by significantly moderating both MAPK (CRAF-ERK axis) and PI3K/AKT pathways, and inducing apoptosis through the mitochondrial pathway and up-regulation of p53. In addition, autophagy inhibition enhances the antitumor efficacy of these PHB ligands. More important, these ligands can act in synergy with MAPKi to more efficiently inhibit cell growth and overcome drug resistance in both BRAF wild-type and mutant melanoma. In conclusion, targeting PHBs represents a very promising therapeutic strategy in melanoma, regardless of mutational status.
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Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Proibitinas , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas B-raf/metabolismo , Ligantes , Inibidores de Proteínas Quinases/farmacologia , Resistencia a Medicamentos AntineoplásicosRESUMO
BACKGROUND: Malignant peritoneal cytology in endometrial cancer (EC) is not considered an independent adverse prognostic factor for uterine-confined disease and is not a determinant factor in the International Federation of Gynecology and Obstetrics (FIGO) staging system. NCCN Guidelines still recommend obtaining cytologies. The aim of this study was to determine the prevalence of peritoneal cytologic contamination following robotic hysterectomy for EC. METHODS: Peritoneal cytology from the pelvis and diaphragm were obtained at the initiation of surgery, and from the pelvis only at the completion of robotic hysterectomy with sentinel lymph node mapping (SLNM). Cytology specimens were evaluated for the presence of malignant cells. Pre- and post-hysterectomy cytology results were compared, and pelvic contamination was defined as conversion from negative to positive cytology following surgery. RESULTS: 244 patients underwent robotic hysterectomy with SLNM for EC. Pelvic contamination was identified in 32 (13.1%) cases. In multivariate analysis, pelvic contamination was associated with >50% myometrial invasion, tumor size >2 cm, lymphovascular space invasion (LVSI), and lymph node metastasis. There was no association with FIGO stage or histology subtypes. CONCLUSIONS: Malignant peritoneal contamination occurred during robotic surgery for EC. Large lesions (>2 cm), deep invasion (>50%), LVSI, and lymph node metastasis were each independently associated with peritoneal contamination. Whether or not peritoneal contamination increases risk for disease recurrence should be studied in larger series, including an evaluation of patterns of recurrence and the potential impact of adjuvant therapies. Until the clinical impact of peritoneal contamination during hysterectomy for EC is better understood, methods to reduce peritoneal contamination are warranted.
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Neoplasias do Endométrio , Procedimentos Cirúrgicos Robóticos , Feminino , Humanos , Linfonodos/patologia , Excisão de Linfonodo/efeitos adversos , Excisão de Linfonodo/métodos , Metástase Linfática/patologia , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Estudos Retrospectivos , Recidiva Local de Neoplasia/patologia , Neoplasias do Endométrio/patologia , Histerectomia/efeitos adversos , Histerectomia/métodos , Estadiamento de NeoplasiasRESUMO
Melanoma is known to be a radioresistant cancer. Melanoma radioresistance can be due to several factors such as pigmentation, antioxidant defenses and high Deoxyribonucleic acid (DNA) repair efficacy. However, irradiation induces intracellular translocation of RTKs, including cMet, which regulates response to DNA damage activating proteins and promotes DNA repair. Accordingly, we hypothesized that co-targeting DNA repair (PARP-1) and relevant activated RTKs, c-Met in particular, may radiosensitize wild-type B-Raf Proto-Oncogene, Serine/Threonine Kinase (WTBRAF) melanomas where RTKs are often upregulated. Firstly, we found that PARP-1 is highly expressed in melanoma cell lines. PARP-1 inhibition by Olaparib or its KO mediates melanoma cell sensitivity to radiotherapy (RT). Similarly, specific inhibition of c-Met by Crizotinib or its KO radiosensitizes the melanoma cell lines. Mechanistically, we show that RT causes c-Met nuclear translocation to interact with PARP-1 promoting its activity. This can be reversed by c-Met inhibition. Accordingly, RT associated with the inhibition of both c-Met and PARP-1 resulted in a synergistic effect not only on tumor growth inhibition but also on tumor regrowth control in all animals following the stop of the treatment. We thus show that combining PARP and c-Met inhibition with RT appears a promising therapeutic approach in WTBRAF melanoma.