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INTRODUCTION: Data about the feasibility or stability of drugs prepared for intrathecal administration are scarce, especially concerning the possibility of mixing two or more compounds in the same syringe. We evaluated the stability of an extemporaneously prepared triple intrathecal therapy containing methotrexate, cytarabine, and methylprednisolone hemisuccinate. MATERIALS AND METHODS: Six mixtures containing 12.5 mg methotrexate, 50 mg cytarabine, and 40 mg methylprednisolone hemisuccinate, diluted to a final volume of 5â ml with water for injection, were prepared in polypropylene syringes on six different days. Syringes were stored protected from light either at room temperature (20°C) (n = 3) or refrigerated temperature (4°C) (n = 3). Samples were analyzed immediately after preparation and again at 0.5, 2, 4, 6, 8, and 24 h. The analysis was conducted with a high-performance liquid chromatography instrument equipped with a quaternary pump and diode array detector. pH was also assessed before every sample analysis. RESULTS: When mixed in a polypropylene syringe, the three drugs were stable at both temperatures tested. No degradation >10% was observed in any sample and pH remained between 7.0 and 7.5 over time. No precipitation or color change occurred. Among the three compounds, methylprednisolone hemisuccinate was the most labile as a slight temperature- and time-dependent degradation was observed. CONCLUSION: Triple intrathecal solution of methotrexate, cytarabine, and methylprednisolone hemisuccinate is stable for up to 24 h when stored in polypropylene syringes protected from light at 4°C and 20°C.
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BACKGROUND: Hypertension is usually associated with increased cardiovascular mortality. Uncertainty exists about the possible role of hypertension as a poor prognostic factor for cancer-specific mortality (CSM). To assess the association between pre-existing hypertension and the risk of mortality and relapse after a diagnosis of cancer, we performed a systematic review and meta-analysis of published studies. METHODS: PubMed, Scopus, Web of Science, the Cochrane Library and EMBASE were searched from inception until May 2020, without language restrictions, for observational studies reporting the prognosis of patients with hypertension and cancer. The primary outcome of the study refers to CSM in hypertensive vs nonhypertensive patients, and secondary endpoints were overall mortality (OM) and progression- or relapse-free survival. The effect size was reported as hazard ratios (HRs) with 95% CIs. RESULTS: Mortality and relapse associated with hypertension in patients with various cancers were evaluated among 1 603 437 participants (n = 66 studies). Overall, diagnosis of cancer and hypertension was associated with an increased independent risk of OM (HR = 1.2 [95% CI, 1.13-1.27], P < .01) and CSM (HR = 1.12 [95% CI, 1.04-1.21], P < .01) but not of relapse (HR = 1.08 [95% CI, 0.98-1.19], P = .14). CONCLUSIONS: Among cancer patients, those with pre-existing hypertension have a poorer outcome, probably due to multifactorial reasons. Adequate control of lifestyle, more intensive follow-ups, monitoring for hypertension- and anticancer-related cardiovascular complications, and establishing multidisciplinary cardio-oncology units can be useful measures for reducing mortality and improving care in this setting.
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Hipertensão/epidemiologia , Neoplasias/mortalidade , Causas de Morte , Comorbidade , Intervalo Livre de Doença , Humanos , Recidiva Local de Neoplasia/epidemiologia , Modelos de Riscos Proporcionais , Taxa de SobrevidaRESUMO
PURPOSE: Established that the only approved agents in previously treated metastatic colorectal cancer (CRC) are trifluoridine/tipiracil and regorafenib, we conducted a systematic review of all the published phase 2-3 trials, with the scope to evaluate the benefit of any later-line regimens in refractory metastatic CRC. METHODS: Phase 2-3 studies that enrolled patients with stage IV disease receiving salvage therapies for refractory CRC were identified using electronic databases (Pubmed, EMBASE, and Cochrane Library). Clinical outcomes were pooled using a point estimates for the weighted values of median overall survival (OS), progression-free survival (PFS), response rate (ORR), stable disease rate (SD), and 6-month and 1-year OS. RESULTS: Overall, 7556 patients were included from 67 studies (n = 70 arms). Overall, the pooled ORR and SD were 15.4% (95% CI 13-18%) and 36.9% (95% CI 33.5-40.6%). Median PFS, 6-month and 1-year OS, and median OS were 3.2 (95% CI 2.9-3.3) months, 65.4% (95% CI 61.9-68.8%), 36% (95% CI 32.3-39.9%) and 8.8 (95% CI 8.3-9.2) months. Overall survival was different in the monochemotherapy, polychemotherapy, chemotherapy + targeted therapy, and targeted therapy alone arms (7.6, 9.5, 10.3, and 7.9 months, respectively, P for difference = 0.01). Median PFS were respectively 2.3, 3.9, 3.8, and 2.6, respectively (P for difference < 0.01). CONCLUSIONS: Overall, combination therapy (polychemotherapy with or without targeted agents) is associated with a higher control of disease and better outcome than approved agents. Treatment, if possible, should be personalized according to the patients' conditions, physician preference and molecular profile of disease.
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Neoplasias Colorretais/secundário , Neoplasias Colorretais/terapia , Terapia de Salvação , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Resultado do TratamentoRESUMO
The use of continuous-infusion in outpatient setting could be widely used in oncology and haematology care. Many times the lack of data stability about single drug or admixture of drugs, together with patient education and safety, make difficult the transition from inpatient to outpatient setting. Nowadays, this is a big challenge for hospital pharmacists, who must take into consideration the critical issues related to chemical and physical stability, besides microbiological one, in order to ensure high quality preparations and guarantee the safety and quality of care, to protect patients and their health. The aim of this article is to highlight the critical issues concerning the transition from inpatient to outpatient setting, with particular interest regarding chemotherapy protocols, which require preparation with long-term continuous-infusion.
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Antineoplásicos/administração & dosagem , Farmacêuticos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Estabilidade de Medicamentos , Humanos , Infusões Intravenosas , Pacientes Internados , Pacientes AmbulatoriaisRESUMO
Olaparib is a first-in-class PARP inhibitor that has demonstrated efficacy as maintenance therapy in patients with ovarian cancer. It has been approved as a capsule formulation and after the publication of data from SOLO2 study became available also as tablet formulation. Due to different pharmacokinetic properties, these different formulations cannot be considered bioequivalent nor interchangeable. The tablet formulation has improved bioavailability, reducing pill burden and offering a more convenient dosage regimen. Furthermore, olaparib tablet formulation had a manageable tolerability profile if compared to capsule one, with most of adverse events of mild or moderate severity. Under this light, olaparib tablet formulation is a useful maintenance strategy for recurrent, platinum-sensitive ovarian cancer, providing a more convenient dosing option than the capsule formulation.
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Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Ftalazinas/administração & dosagem , Ftalazinas/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Adulto , Disponibilidade Biológica , Cápsulas , Composição de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , ComprimidosRESUMO
In urothelial cancer of the bladder, the introduction of immunotherapy with immune checkpoint inhibitors represents progress in the management of the disease's early and advanced stages. In particular, recent studies have implemented these drugs in the neoadjuvant and adjuvant phases to treat muscle-invasive bladder cancer. In some studies, patients received neoadjuvant immune checkpoint inhibitors alone (PURE and ABACUS) to treat muscle invasive bladder cancer, whereas other studies provided this therapy to cisplatin-ineligible patients. Furthermore, a large Phase III study (CheckMate 247) compared placebo with adjuvant nivolumab therapy in patients with high-risk urothelial cancer after neoadjuvant chemotherapy and surgery or surgery alone. Despite some uncertain niches (nonbladder, PD-L1-negative tumors, and node-negative resected cancers), certain biological opportunities (exploring new targets, evaluating in vivo pathologic response, focusing on biomarkers for response) and clinical uses (avoiding chemotherapy at all or in frail patients, attaining similar pathologic complete response rates as in cisplatin-based chemotherapy) are valid reasons for incorporating these agents into the therapeutic armamentarium of medical uro-oncologists.
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Neoplasias da Bexiga Urinária , Antígeno B7-H1 , Biomarcadores , Quimioterapia Adjuvante , Cisplatino/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Terapia Neoadjuvante , Nivolumabe/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologiaRESUMO
Among pre- and postmenopausal women with hormone receptor-positive (HR+) breast cancer (BC), combinations of an aromatase inhibitor (AI) or fulvestrant with a CDK 4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) have demonstrated improved progression-free survival (PFS) and overall survival (OS) compared to standard single-agent hormone therapy alone as first-line therapy for de novo metastatic disease or relapse during or after adjuvant therapy and no previous therapies in an advanced setting. We here reviewed clinical data about ribociclib in advanced and early BC. Also, we shed light on patient selection and special settings in which medical oncologists urgently await an advance in treatment. Ribociclib was FDA-approved in combination with letrozole based on a Phase III study in which 668 postmenopausal women with HR+, HER2-negative recurrent or metastatic BC were treated with first-line letrozole with or without ribociclib. For patients with metastatic disease at presentation or after a course of AIs, the results of the MONALEESA-3 trial suggest ribociclib's efficacy in combination with fulvestrant, and this combination is FDA-approved for initial- and subsequent-line endocrine therapy for postmenopausal women with metastatic hormone receptor-positive, HER2-negative BC. In adjuvant and neoadjuvant settings, the use of CDK 4/6 inhibitors may be useful to boost outcomes in high-risk patients with HR+ BC, but data contrast with those of a phase III study, which produced positive results. New combinations are being explored in upfront disease (neoadjuvant) or in association with other targeted agents in metastatic disease. Compared to other CDK 4/6 available, ribociclib has a higher incidence of liver function test abnormalities than the other agents and can cause QTc prolongation, and therefore may be prudently avoided in patients with cardiac morbidities or other risk factors for QTc prolongation (drugs, interactions). In these cases, different agents (palbociclib or abemaciclib) may be used. In conclusion, ribociclib with letrozole or with fulvestrant is effective for the entire spectrum of patients with HR+ BC in the advanced setting. Ribociclib has all the characteristics of an innovative drug able to change the clinical practice and most BC patients' prognoses.
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Immunotherapeutic drugs and target therapies have represented an epochal change in treating cancer patients. They represent an attractive option in oncologists' armamentarium, particularly if we consider the optimal balance between efficacy and toxicity. As a step forward, immuno- and target-therapies have merged intending to improve efficacy: antibody-drug conjugates ensure the perfect combination. They allow the delivery of large amounts of drugs to the target with a limited 'off-target' effect and a low rate of adverse events. These aspects could make immunoconjugates palatable as the first choice for fragile patients, but solid evidence does not exist on the use of these drugs in this population type, especially older people.
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Antineoplásicos , Imunoconjugados , Neoplasias , Idoso , Antineoplásicos/efeitos adversos , Humanos , Imunoconjugados/efeitos adversos , Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: The majority of patients with coronavirus disease 2019 (COVID-19) have good prognoses, but some develop a critical illness that can lead to death. Evidence shows severe acute respiratory syndrome is closely related to the induced cytokine storm. Interleukin-6 is a key player; its role in systemic inflammation is well known. AIM: To evaluate the effect of tocilizumab (TCZ), an interleukin-6 receptor antagonist, on the outcomes for patients with COVID-19 pneumonia. METHODS: PubMed, EMBASE, SCOPUS, Web of Science, MedRxiv, Science Direct, and the Cochrane Library were searched from inception to 9th June 2020 for observational or prospective studies reporting results of hospitalized adult patients with COVID-19 infection treated with TCZ. Effect sizes were reported as odds ratios (ORs) with 95% confidence intervals (CIs), and an OR less than 1 was associated with a better outcome in those treated with TCZ. RESULTS: Overall 13476 patients (33 studies; n = 3264 received TCZ) with COVID-19 pneumonia and various degree of severity were included. Outcome was improved with TCZ. In the primary analysis (n = 19 studies reporting data), mortality was reduced in patients treated with TCZ (OR = 0.64, 95%CI: 0.47-0.87; P < 0.01). In 9 studies where risk of death with TCZ use was controlled for other variables mortality was reduced by 57% (OR = 0.43, 95%CI: 0.27-0.7; P < 0.01). Intensive care need (mechanical ventilation) was also reduced (OR = 0.36, 95%CI: 0.14-0.89; P = 0.02). CONCLUSION: In COVID-19-infected patients treated with TCZ, outcome may be improved compared to those not treated with TCZ.
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Biliary tract cancer is an uncommon cancer in developed countries. In localized stages, surgery is the cornerstone of treatment with curative purpose. Conversely in advanced stages, chemotherapy with platinum-gemcitabine combination is the standard of care. Biliary tract cancers are a biologically heterogeneous group of malignancies, which perhaps explains the failure of targeted therapies in unselected patient populations to demonstrate benefit in advanced disease, although there are promises in selected populations (e.g. PD1/PD-L1 positive, BRAFV600E-mutated or IDH1-mutant). In view of the limited benefit of second line therapies in metastatic biliary tract cancer, various targeted agents have been tested in progressive disease. Furthermore, several ongoing trials are using next-generation sequencing of multiple genes to identify molecular abnormalities in the tumors of patients with refractory cancers that may potentially be used in pretreated disease (e.g. FGFR or IDH genes). Immunotherapy with immune checkpoint inhibitors may be interesting for patients whose tumors have programmed cell death 1 ligand 1 (PD-L1) overexpression. Ongoing and future trials will further advance our knowledge toward the optimal treatment strategy for the management of biliary tract cancer in its different stages, starting from metastatic and then reaching early stages of disease. We here provided an overview of these novel treatment strategies for advanced biliary tract cancers not amenable of curative treatment modalities.
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Neoplasias do Sistema Biliar/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/mortalidade , Ensaios Clínicos como Assunto , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/antagonistas & inibidoresRESUMO
Vitamin D modulates the systemic inflammatory response through interaction with immune system. As such, it has a possible protective role against the risk of respiratory tract infections and other diseases. It may be useful in particular, during COVID-19 pandemic. PubMed, the Cochrane Library, and EMBASE were searched from inception until January 31, 2021, for observational or clinical studies reporting the prognosis (and therapeutic effect) of COVID-19 infection in patients with deficient vitamin D levels. The infection rate, severity, and death from COVID-19 infection were pooled to provide an odds ratio with a 95 % confidence interval (OR 95 % CI). An OR > 1 was associated with the worst outcome in deficient compared with nondeficient patients. We assessed the association between vitamin D and risk, severity, and mortality for COVID-19 infection, through a review of 43 observational studies. Among subjects with deficient vitamin D values, risk of COVID-19 infection was higher compared to those with replete values (OR = 1.26; 95 % CI, 1.19-1.34; P < .01). Vitamin D deficiency was also associated with worse severity and higher mortality than in nondeficient patients (OR = 2.6; 95 % CI, 1.84-3.67; P < .01 and OR = 1.22; 95 % CI, 1.04-1.43; P < .01, respectively). Reduced vitamin D values resulted in a higher infection risk, mortality and severity COVID-19 infection. Supplementation may be considered as preventive and therapeutic measure.
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COVID-19/epidemiologia , Suplementos Nutricionais , Pandemias , SARS-CoV-2/patogenicidade , Deficiência de Vitamina D/epidemiologia , Vitamina D/uso terapêutico , COVID-19/sangue , COVID-19/mortalidade , COVID-19/prevenção & controle , Humanos , Imunidade Inata/efeitos dos fármacos , Incidência , Estudos Observacionais como Assunto , Razão de Chances , Prognóstico , Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/mortalidade , Deficiência de Vitamina D/prevenção & controleRESUMO
Background: Rare cancers, as defined by the European Union, occur in fewer than 15 out of 100,000 people each year. The International Rare Cancer Consortium defines rare cancer incidence as less than six per 100,000 per year. There is a growing number of reports of the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with rare tumours, and hence, we conducted a comprehensive review to summarise and analyse the available literature. Methods: A literature search of PubMed was performed on January 31, 2021, using the following ICI names as keywords: ipilimumab, tremelimumab, cemiplimab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab. Studies on patients with rare tumours who were being treated with ICIs were included. We plotted the overall response rate against the corresponding median survival across a variety of cancer types using linear regression. Results: From 1,255 publications retrieved during the primary search, 62 publications were selected (with a total of 4,620 patients). Only four were randomised trials. A minority were first-line studies, while the remaining were studies in which ICIs were delivered as salvage therapy in pretreated patients. There was a good correlation between response rate and overall survival (Spearman R2 >0.9) in skin cancers, mesothelioma, and sarcomas. Conclusions: Treatment of advanced-stage rare tumours with ICI therapy was found to be associated with significant activity in some orphan diseases (e.g., Merkel cell carcinoma) and hepatocellular carcinoma. Several ongoing prospective clinical trials will expand the knowledge on the safety and efficacy of ICI therapy in patients with these rare cancers.
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Inibidores de Checkpoint Imunológico/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Proteínas de Checkpoint Imunológico/genética , Proteínas de Checkpoint Imunológico/metabolismo , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Neoplasias/diagnóstico , Neoplasias/etiologia , Neoplasias/mortalidade , Especificidade de Órgãos , Prognóstico , Doenças Raras , Resultado do TratamentoRESUMO
First-line treatment for metastatic clear-cell renal cell carcinoma patients with intermediate and poor-risk features consists of a combination of immune checkpoint inhibitors (e.g., nivolumab + ipilimumab) or immunotherapy with an anti-vascular endothelial growth factor receptor (VEGFR) drug (e.g., axitinib). The subsequent line of therapy should be determined on the basis of previous treatments and approved drugs available, based on the results of randomized clinical trials. Unfortunately, no phase 3 trial has compared the safety and efficacy of drugs after immunotherapy; thus, drug choice is more empirical than evidence-based. As the tumor may still be anti-VEGFR drug-naïve, a tyrosine kinase inhibitor approved for first line treatment (e.g., sunitinib or pazopanib) may be beneficial. Because this is a second-line treatment, patients could also receive axitinib, cabozantinib, or a combination of lenvatinib and everolimus. The treating physician should choose an appropriate treatment according to the patient's age, comorbidities, and tolerability of previous checkpoint inhibitors, among other considerations. Cases of patients with renal cell carcinoma refractory to checkpoint inhibitor treatment are growing, warranting a review of the activity and safety of target therapies after immunotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/terapia , Imunoterapia/métodos , Neoplasias Renais/terapia , Terapia de Alvo Molecular/métodos , Anilidas/administração & dosagem , Axitinibe/administração & dosagem , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Ensaios Clínicos como Assunto , Humanos , Indazóis , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Metástase Neoplásica , Nivolumabe/administração & dosagem , Seleção de Pacientes , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Quinolinas/administração & dosagem , Sulfonamidas/administração & dosagem , Sunitinibe/administração & dosagemRESUMO
BACKGROUND: Steroids are commonly used in patients with solid tumours for supportive therapy. In other cases, they are an essential part of cancer treatment such as prostate cancer. Some preclinical observations lead to the notion that glucocorticoids may modulate growth factors' pathways and may induce the progression of cancers. Glucocorticoids are associated with several side-effects on many organ systems (e.g. serious infections, diabetes, sepsis and thrombosis). We have performed a systematic review and meta-analysis to evaluate the outcome of cancer patients that assume or not steroids. METHODS: Published articles that evaluated survival associated with steroids use in cancer patients from inception to June 2020 were identified by searching the PubMed, EMBASE and Cochrane Library databases. The primary outcome of interest was the risk of death, and the secondary end-point was the risk of progression in steroid versus non-steroid users. RESULTS: Seventy-six studies were in quantitative synthesis for a total of 83,614 patients. Use of steroids was associated with a reduced survival (hazard ratios (HR) = 1.18, 95% confidence interval (CI): 1.1-1.26; P < .01). Progression-free survival was also decreased in steroid versus non-steroid users (HR = 1.13, 95% CI: 1.01-1.26; P = .03). In patients with lung cancer, advanced disease and supportive care indications were settings where the use of steroids increased the risk of death. CONCLUSIONS: In patients with advanced cancers, use of steroids should be reduced and, at best, avoided because it may reduce survival, in particular, for patients with lung cancer and for palliative/supportive care purposes.
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Glucocorticoides/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Humanos , Intervalo Livre de ProgressãoRESUMO
Antibiotics (ABs) are common medications used for treating infections. In cancer patients treated with immune checkpoint inhibitors (ICIs), concomitant exposure to ABs may impair the efficacy of ICIs and lead to a poorer outcome compared to AB non-users. We report here the results of a meta-analysis evaluating the effects of ABs on the outcome of patients with solid tumours treated with ICIs. PubMed, the Cochrane Library and Embase were searched from inception until September 2019 for observational or prospective studies reporting the prognoses of adult patients with cancer treated with ICIs and with or without ABs. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The effect size was reported as hazard ratios (HRs) with a 95% confidence interval (CI) and an HR > 1 associated with a worse outcome in ABs users compared to AB non-users. Fifteen publications were retrieved for a total of 2363 patients. In the main analysis (n = 15 studies reporting data), OS was reduced in patients exposed to ABs before or during treatment with ICIs (HR = 2.07, 95%CI 1.51-2.84; p < 0.01). Similarly, PFS was inferior in AB users in n = 13 studies with data available (HR = 1.53, 95%CI 1.22-1.93; p < 0.01). In cancer patients treated with ICIs, AB use significantly reduced OS and PFS. Short duration/course of ABs may be considered in clinical situations in which they are strictly needed.