Treatment and Implications of Vascular Endothelial Growth Factor Inhibitor-Induced Blood Pressure Rise: A Clinical Cohort Study.

Background Anti-cancer vascular endothelial growth factor inhibitors (VEGFI) frequently induce a rise in blood pressure (BP). The most effective treatment of this BP rise is currently unknown, and risk factors and its association with survival remain inconclusive. Methods and Results Baseline characteristics and BP readings were retrospectively collected from oncology patients who received oral VEGFI treatment (sorafenib, sunitinib, pazopanib, regorafenib, lenvatinib, or cabozantinib). Risk factors for a clinically relevant BP rise (increase of ≥20 mm Hg in systolic BP or ≥10 mm Hg in diastolic BP) were investigated via logistic regression (relative), efficacy of antihypertensives via unpaired t-tests, and association of BP rise with survival via Cox regression analysis. In total, 162 (47%) of 343 included patients developed a clinically relevant BP rise ≥7 days after VEGFI treatment initiation. Both calcium channel blockers and renin-angiotensin system inhibitors effectively reduced systolic BP (-24.1 and -18.2 mm Hg, respectively) and diastolic BP (-12.0 and -11.0 mm Hg, respectively). Pazopanib therapy (odds ratio, 2.71 [95% CI, 1.35-5.42; P=0.005], compared with sorafenib) and estimated glomerular filtration rate <60 mL/min per 1.73 m2 (OR, 1.75 [95% CI, 0.99-3.18, P=0.054]) were risk factors for a BP rise, whereas a baseline BP ≥140/90 mm Hg associated with a lower risk (OR, 0.39 [95% CI, 0.25-0.62, P<0.001]). Only for renal cell carcinoma, BP rise was associated with a substantially improved median overall survival compared with no BP rise: 45.4 versus 20.3 months, respectively, P=0.003. Conclusions The type of VEGFI, baseline BP, and baseline estimated glomerular filtration rate determine the VEGFI-induced BP rise. Both calcium channel blockers and renin-angiotensin system inhibitors are effective antihypertensive treatments. Particularly in patients with renal cell carcinoma, a BP rise is associated with improved overall survival.

Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial.

BACKGROUND: Understanding patients' experience of cancer treatment is important. We aimed to evaluate patient-reported outcomes (PROs) with atezolizumab plus bevacizumab versus sorafenib in patients with advanced hepatocellular carcinoma in the IMbrave150 trial, which has already shown significant overall survival and progression-free survival benefits with this combination therapy. METHODS: We did an open-label, randomised, phase 3 trial in 111 hospitals and cancer centres across 17 countries or regions. We included patients aged 18 years or older with systemic, treatment-naive, histologically, cytologically, or clinically confirmed unresectable hepatocellular carcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with disease that was not amenable to curative surgical or locoregional therapies, or progressive disease after surgical or locoregional therapies. Participants were randomly assigned (2:1; using permuted block randomisation [blocks of six], stratified by geographical region; macrovascular invasion, extrahepatic spread, or both; baseline alpha-fetoprotein concentration; and ECOG performance status) to receive 1200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously once every 3 weeks or 400 mg sorafenib orally twice a day, until loss of clinical benefit or unacceptable toxicity. The independent review facility for tumour assessment was masked to the treatment allocation. Previously reported coprimary endpoints were overall survival and independently assessed progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1. Prespecified secondary and exploratory analyses descriptively evaluated treatment effects on patient-reported quality of life, functioning, and disease symptoms per the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ-C30) and quality-of-life questionnaire for hepatocellular carcinoma (QLQ-HCC18). Time to confirmed deterioration of PROs was analysed in the intention-to-treat population; all other analyses were done in the PRO-evaluable population (patients who had a baseline PRO assessment and at least one assessment after baseline). The trial is ongoing; enrolment is closed. This trial is registered with ClinicalTrials.gov, NCT03434379. FINDINGS: Between March 15, 2018, and Jan 30, 2019, 725 patients were screened and 501 patients were enrolled and randomly assigned to atezolizumab plus bevacizumab (n=336) or sorafenib (n=165). 309 patients in the atezolizumab plus bevacizumab group and 145 patients in the sorafenib group were included in the PRO-evaluable population. At data cutoff (Aug 29, 2019) the median follow-up was 8·6 months (IQR 6·2-10·8). EORTC QLQ-C30 completion rates were 90% or greater for 23 of 24 treatment cycles in both groups (range 88-100% in the atezolizumab plus bevacizumab group and 80-100% in the sorafenib group). EORTC QLQ-HCC18 completion rates were 90% or greater for 20 of 24 cycles in the atezolizumab plus bevacizumab group (range 88-100%) and 21 of 24 cycles in the sorafenib group (range 89-100%). Compared with sorafenib, atezolizumab plus bevacizumab reduced the risk of deterioration on all EORTC QLQ-C30 generic cancer symptom scales that were prespecified for analysis (appetite loss [hazard ratio (HR) 0·57, 95% CI 0·40-0·81], diarrhoea [0·23, 0·16-0·34], fatigue [0·61, 0·46-0·81], pain [0·46, 0·34-0·62]), and two of three EORTC QLQ-HCC18 disease-specific symptom scales that were prespecified for analysis (fatigue [0·60, 0·45-0·80] and pain [0·65, 0·46-0·92], but not jaundice [0·76, 0·55-1·07]). At day 1 of treatment cycle five (after which attrition in the sorafenib group was more than 50%), the mean EORTC QLQ-C30 score changes from baseline in the atezolizumab plus bevacizumab versus sorafenib groups were: -3·29 (SD 17·56) versus -5·83 (20·63) for quality of life, -4·02 (19·42) versus -9·76 (21·33) for role functioning, and -3·77 (12·82) versus -7·60 (15·54) for physical functioning. INTERPRETATION: Prespecified analyses of PRO data showed clinically meaningful benefits in terms of patient-reported quality of life, functioning, and disease symptoms with atezolizumab plus bevacizumab compared with sorafenib, strengthening the combination therapy's positive benefit-risk profile versus that of sorafenib in patients with unresectable hepatocellular carcinoma. FUNDING: F Hoffmann-La Roche and Genentech.

Mechanisms of the antiangiogenic effects of aspirin in cancer.

Aspirin is an old drug extracted from willow bark and is widely used for the prevention and treatment of cardiovascular diseases. Accumulating evidence has shown that aspirin use may significantly reduce the angiogenesis of cancer; however, the mechanism of the association between angiogenesis and aspirin is complex. Although COX-1 is widely known as a target of aspirin, several studies reveal other antiangiogenic targets of aspirin, such as angiotensin II, glucose transporter 1, heparanase, and matrix metalloproteinase. In addition, some data indicates that aspirin may produce antiangiogenic effects after acting in different cell types, such as endothelial cells, platelets, pericytes, and macrophages. In this review, we concentrate on research regarding the antiangiogenic effects of aspirin in cancer, and we discuss the molecular mechanisms of aspirin and its metabolites. Moreover, we discuss some mechanisms through which aspirin treatment may normalize existing blood vessels, including preventing the disintegration of endothelial adheres junctions and the recruitment of pericytes. We also address the antiangiogenic effects and the underlying mechanisms of aspirin derivatives, which are aimed at improving safety and efficacy.

Mingjing granule, a traditional Chinese medicine in the treatment of neovascular age-related macular degeneration: study protocol for a randomized controlled trial.

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is the most common cause of irreversible vision loss and blindness among the older people aged 50 and over. Although anti-vascular endothelial growth factor (anti-VEGF) therapies have resulted in improving patient outcomes, there are limitations associated with these treatments. In China, traditional Chinese medicine (TCM) has been used to treat eye diseases for more than 2000 years. Previous studies have shown that TCM may be beneficial for nAMD patients. However, explicit evidence has not been obtained. The purpose of the present trial is to examine the efficacy and safety of the Mingjing granule, a compound Chinese herbal medicine, for nAMD patients. METHODS/DESIGN: This is a double-blind, placebo-controlled, randomized trial of Mingjing granule as an add-on to intravitreous ranibizumab for nAMD. One hundred eighty nAMD patients from six hospitals in China will be enrolled according to the inclusion and exclusion criteria and randomly allocated into two groups, 90 in each. All participants will receive a 24-week treatment and then be followed up for another 24 weeks. The primary outcome is the mean change of best-corrected visual acuity at week 24 and 48 as compared to the baseline. The secondary outcomes include mean change in central retinal thickness, area of retinal hemorrhage and exudation, and TCM syndrome score, mean number of intravitreal ranibizumab injection, and total cost of the treatment. Indexes of safety include blood regular test, urine regular test, liver function test, renal function test, and electrocardiogram from baseline to weeks 24 and 48. Qualitative control and some standard operating processes will be formed throughout the trial. Any ocular or systemic adverse events will be treated suitably, and related data will be recorded accurately and completely in the case report form. DISCUSSION: Based on previous empirical and animal laboratory studies, this study will address the question of whether Mingjing granule could contribute to improving efficacy, safety, and efficiency with need for fewer intravitreal injections of anti-VEGF, improving compliance and visual outcomes in the management of persons with nAMD. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn ), ChiCTR2000035990 . Registered on 21 August 2020.

Preclinical Efficacy and Safety of VEGF-Grab, a Novel Anti-VEGF Drug, and Its Comparison to Aflibercept.

Purpose: VEGF-Grab is a novel anti-vascular endothelial growth factor (VEGF) candidate drug with higher affinity to both VEGF and placental growth factor (PlGF) compared to aflibercept. We investigated the preclinical efficacy of VEGF-Grab for ophthalmic therapy and compared it to that of aflibercept. Methods: The in vitro anti-VEGF efficacy of VEGF-Grab was determined using VEGF-induced cell proliferation/migration and tube formation assays. The in vivo antiangiogenic efficacy of intravitreal injection of either VEGF-Grab or aflibercept was evaluated using murine models of ocular angiogenesis: mouse oxygen-induced retinopathy (OIR) and rat laser-induced choroidal neovascularization (CNV). The in vivo retinal toxicity in the mouse eye resulting from the injection of either drug was evaluated with light and electron microscopy. Results: VEGF-Grab showed greater inhibition of VEGF-induced cell proliferation/migration than aflibercept, but it showed comparable inhibition of tube formation in vitro. In the in vivo OIR model, VEGF-Grab showed a comparable suppression of retinal neovascularization compared to aflibercept. Additionally, VEGF-Grab showed an efficacy similar to that of aflibercept in terms of CNV inhibition in the laser-induced CNV model. Histology and transmission electron microscopy showed no significant signs of toxicity in the mouse retina at 7 and 30 days following the intravitreal injection of VEGF-Grab or aflibercept. Conclusions: Compared to aflibercept, VEGF-Grab presented comparable in vivo antiangiogenic efficacy and superior in vitro anti-VEGF activity. The retinal safety profiles were comparable for the two drugs. Considering its known higher binding affinity to VEGF and PlGF compared to aflibercept, VEGF-Grab could be a potential candidate drug for neovascular retinal diseases and an alternative to aflibercept.

The Vascular Component of Melasma: A Systematic Review of Laboratory, Diagnostic, and Therapeutic Evidence.

BACKGROUND: Melasma is a common acquired disorder of hyperpigmentation, classically manifesting as symmetric brown patches on the face. Although the exact pathogenesis is not fully understood, vascular abnormalities have been implicated in melasma. OBJECTIVE: To evaluate the laboratory and clinical evidence regarding the safety and efficacy of antivascular agents for the treatment of melasma. METHODS: A systematic review of PubMed, EMBASE, and Cochrane was conducted on May 13, 2020, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Original research articles investigating the role of vascularity and/or evaluating the use of antivascular therapeutics in melasma were included. Clinical recommendations were based on the American College of Physicians guidelines. RESULTS: A total of 34 original research articles as follows were identified: 4 laboratory studies, 15 diagnostic studies, and 15 therapeutic studies. CONCLUSION: There is promising evidence supporting the use of tranexamic acid and laser/light therapies to treat the vascular component of melasma, and more rigorous clinical trials are needed to validate their efficacy. Clinicians may consider treatment with one or more antivascular therapeutics in patients with melasma. Further research is warranted to characterize the role of cutaneous vascularization in melasma and may provide insights for novel therapies.

Real-world outcomes with ranibizumab in branch retinal vein occlusion: The prospective, global, LUMINOUS study.

OBJECTIVE: To evaluate the effectiveness, safety, and treatment patterns of ranibizumab 0.5 mg in treatment-naïve patients with branch retinal vein occlusion (BRVO) enrolled in the LUMINOUS™ study. STUDY DESIGN: A 5-year, global, prospective, multicenter, observational, open-label study conducted in a clinical practice (real-world) setting at outpatient ophthalmology clinics that recruited 30,138 consenting adult patients from all approved indications for ranibizumab across 42 countries. Patients with BRVO were treated according to the local ranibizumab label of the participating countries. Mean change in visual acuity (VA) in Early Treatment Diabetic Retinopathy Study letters from baseline to Year 1, treatment exposure during Year 1, and adverse events (AEs) over 5 years were assessed. RESULTS: Of the 1366 recruited BRVO patients, 405 were treatment-naïve at baseline with a mean (standard deviation [SD]) age of 67.9 (12.5) years, 57.5% were female, and 71.8% were White. At Year 1 (n = 189), the mean (SD) VA gain was 11.9 (17.66) letters from a baseline of 49.2 (±20.32) letters with a mean (SD) of 5.0 (2.34) injections. VA gains were higher in patients (n = 83) who received 6-9 injections (13.6 [20.16] letters) than in those who received 2-5 injections (n = 92, 11.7 [15.43] letters), or 1 injection (n = 14, 3.6 [13.72] letters). Patients with baseline VA <23 letters had numerically highest VA gains (n = 20, 31.1 [24.48] letters). Over 5 years, the rate of ocular/non-ocular AEs was 7.4%/9.1% and serious AEs was 0.3%/4.4% in treatment-naïve BRVO patients (n = 405). CONCLUSIONS: One year results from the LUMINOUS real-world study showed a clinically meaningful VA improvement with ranibizumab in treatment-naïve patients with BRVO; numerically higher VA gains were achieved in patients who received more injections and those with poor baseline VA. No new safety signals were observed.

Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs.

Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in various tumors, particularly in patients affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) comprise a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with metastatic RCC (mRCC). In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of mRCC, highlighting the relevant differences; moreover we aim to define the main pharmacologic characteristics of these drug.

Is there truly an increase in risk of cardiovascular and hematological adverse events with vascular endothelial growth factor receptor tyrosine kinase inhibitors?

Objectives: Recent studies have shown an increase risk of cardiovascular and hematological adverse events associated with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). The authors hypothesize that the original studies may have produced exaggerated results because of the small baseline risks involved.Methods: A meta-analysis that included 71 trials, 8 different VEGFR-TKIs, and 11 adverse events were re-analyzed. The outcome of interest was re-defined as the complementary outcome (i.e. remaining free of an adverse event). The inverse variance heterogeneity model was used to pool the effect size.Results: VEGFR-TKIs decreased the risk of remaining free of hypertension by 7% (RR 0.93; 95%CI:0.88-0.97). Specific VEGFR-TKIs; pazopanib, regorafenib, and nintedanib were associated with a decrease risk of remaining free of an arterial thrombotic event (RR 0.96; 95%CI:0.93-0.99), thrombocytopenia (RR 0.91; 95%CI:0.89-0.93), and bleeding (RR 0.96; 95%CI:0.93-0.99) respectively. VEGFR-TKIs were not associated with the thrombotic event, myocardial infarction, stroke, venous thrombotic event, pulmonary embolism, left ventricular dysfunction, or QTc interval prolongation.Conclusion: VEGFR-TKIs are associated with a small increase in the risk of patients developing hypertension, arterial thrombotic events, thrombocytopenia, and bleeding. Previous studies overestimated the actual risk associated with VEGFR-TKIs by analyzing the outcome with the lower baseline risk.

Eficacia y seguridad de nivolumab en pacientes con carcinoma renal de células claras avanzado, irresecable, con progresion a dos líneas de terapia anti-angiogenica / Efficacy and safety of nivolumab in patients with unresectable advanced clear cell renal cell carcinoma with progression to two lines of anti-angiogenic therapy

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de nivolumab para el tratamiento de pacientes adultos con carcinoma de células renales de células claras (CCRcc) avanzado, irresecable, con progresión de enfermedad a dos líneas de tratamiento sistémico previo con terapia anti-angiogénica, en comparación con la mejor terapia de soporte paliativo (MTSP). El carcinoma de células renales (CCR) representa el 2 % al 3 % de todas las neoplasias malignas en los adultos y la gran mayoría corresponde al subtipo histológico de células claras (CCRcc) (cerca del 75 %). Alrededor del 30 % de los pacientes con CCRcc se presentan en estadios avanzados al momento del diagnóstico. Además, en el 90 % de estos tumores existe un aumento de la señal angiogénica (mutación que activa el factor de crecimiento del endotelio vascular o VEGF). En ese sentido, los tratamientos actuales están dirigidos a inhibir la señal del VEGF con el uso de la terapia anti-angiogénica (e. g. inhibidores de tirosina quinasa [sunitinib, sorafenib, axitinib] o anticuerpos monoclonales contra el receptor del VEGF [bevacizumab]). El Petitorio Farmacológico de EsSalud cuenta con sunitinib como terapia anti-angiogénica para el tratamiento de primera línea de los pacientes con CCRcc avanzado. Luego de la progresión o intolerancia, se opta por el uso de la mejor terapia de soporte paliativo (MTSP) dado que no existe otra alternativa de tratamiento. No obstante, existen algunos pacientes que pueden haber recibido otra terapia anti-angiogénica fuera de la institución como tratamiento de segunda línea luego de progresión a terapia de primera línea. Así, los especialistas han solicitado la evaluación de nivolumab como una alternativa a la MTSP para los pacientes con CCRcc avanzado que hayan recibido dos líneas de tratamiento con terapia anti-angiogénica, sustentando que nivolumab ofrecería un beneficio adicional con respecto a la sobrevida global. METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva y jerárquica de la literatura con respecto a la eficacia y seguridad del nivolumab para pacientes con CCRcc avanzado, irresecable, con progresión a dos líneas de tratamiento sistémico previo con terapia anti-angiogénica (i. e. inhibidores de la tirosina quinasa del receptor VEGF o anticuerpo monoclonal anti-VEGF); comparado con la mejor terapia de soporte paliativo. La búsqueda se inició revisando la información sobre el uso del medicamento de acuerdo con entidades reguladoras como FDA, EMA, y DIGEMID en el Perú. Además, se realizó una búsqueda sistemática en las principales bases de datos, tales como MEDLINE vía PubMed y en Cochrane Library. Así mismo, se realizó una búsqueda manual en las páginas web de grupos dedicados a la investigación y educación en salud que elaboran guías de práctica clínica y/o evaluación de tecnologías sanitarias: National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health - pan-Canadian Oncology Drug Review (pCORD - CADTH), Scottish Medicines Consortium (SMC), Haute Authorité de Santé, la Institute for Quality and Efficiency in Health Care, y la Institute for Clinical and Economic Review el Ministerio de Salud del Perú. Además, se realizó una búsqueda de las guías de las principales sociedades o instituciones especializadas en cáncer, tales como el Instituto Nacional de Enfermedades Neoplásicas (INEN) del Perú, la National Comprehensive Cancer Network (NCCN), la American Society of Clinical Oncology, American Cancer Society, European Society for Medical Oncology (ESMO), Association for Cancer Physicians, Association of European Cancer Leagues, Cancer Australia, Cancer Counsil Australia, Canadian Cancer Society y Health Canada. Por último, se buscaron ensayos clínicos en desarrollo o que no hayan sido publicados en la página web www.clinicaltrials.gov que contengan estudios acerca de la tecnología evaluada, y así disminuir el sesgo de publicación. RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de nivolumab como tratamiento de pacientes con CCRcc avanzado, irresecable, con progresión a dos líneas de tratamiento sistémico previo con terapia anti-angiogénica; comparado con la MTSP. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: El presente dictamen evaluó la mejor evidencia disponible en la actualidad en relación con la eficacia y seguridad de nivolumab comparada con la MTSP en pacientes adultos con CCRcc avanzado, irresecable, con progresión a dos líneas de tratamiento previo con terapia anti-angiogénica. Las guías de NCCN y EAU recomiendan nivolumab como tratamiento de la población de la pregunta PICO, mientras que ESMO recomienda que este grupo de pacientes sean reclutados en un ECA. Además, NCCN recomienda la MTSP en los pacientes que no son candidatos para recibir terapia subsecuente. La tres ETS incluidas recomendaron el uso de nivolumab para los pacientes con CCR avanzado luego de dos líneas de tratamiento sistémico previo con terapia anti-angiogénica, condicionado a un descuento sobre el precio del medicamento acordado de manera confidencial con el laboratorio que lo manufactura. Sin embargo, estas recomendaciones no pueden transferirse directamente al contexto de EsSalud, dado que las características de los sistemas de salud de estos países y su contexto difieren del nuestro. Todos los documentos basaron sus recomendaciones en el ECA CheckMate 025, el cual comparó nivolumab con everolimus para el tratamiento de los pacientes adultos con CCRcc avanzado, con progresión a una y dos líneas de tratamiento previo con terapia anti-angiogénica. Dicho ensayo constituye evidencia indirecta dado que la población de la pregunta PICO (i. e. pacientes con CCRcc avanzado que habían recibido dos líneas de terapia anti-angiogénica previa) está representada sólo por el 28 % de los pacientes incluidos en el estudio; mientras que el comparador, everolimus, no corresponde al comparador de la pregunta PICO (i. e. MTSP). Dichos resultados corresponden a un análisis interino con el 70 % de madurez de la data de mortalidad. Según el Dictamen Preliminar N° 017-SDEPFyOTS-DETS-IETSI-2017, en la población total del ensayo CheckMate 025, luego de hacer la corrección por sobrestimación en desenlaces truncados, no se evidencio una diferencia estadísticamente significativa en SG entre nivolumab y everolimus. Asimismo, el análisis exploratorio del subgrupo de interés del presente dictamen preliminar tampoco mostró diferencias estadísticamente significativas entre nivolumab y everolimus en la sobrevida global. Si bien no se reportaron los resultados de calidad de vida y de eventos adversos en la población de interés, en la población total del estudio no se observaron diferencias clínicamente relevantes en la calidad de vida, ni diferencias estadísticamente significativas en las tasas de EA serios, EA totales y descontinuación de tratamiento debido a EA. Para asumir una comparación indirecta entre nivolumab y la MTSP, el Equipo Técnico del IETSI tuvo en cuenta los resultados generales del estudio CheckMate 025 (nivolumab en comparación con everolimus) y el estudio RECORD-1 (everolimus en comparación con la MTSP), utilizando everolimus como comparador en común. Ambos estudios fueron evaluados previamente en el Dictamen Preliminar N° 004-SDEPFyOTS-DETS-IETSI-2017 (ECA RECORD-1) y el Dictamen Preliminar N° 017-SDEPFyOTS-DETS-IETSI-2017 (ECA CheckMate 025), y tuvieron similares criterios de selección de la muestra, y similares proporciones de pacientes que calzan de manera exacta a la población de interés del presente dictamen preliminar. Así, se tiene que en el ECA RECORD-1 no se observaron diferencias entre everolimus y la MTSP en la SG y la calidad de vida, pero everolimus se asoció con una mayor tasa de descontinuación del tratamiento debido a EA, en la población total del estudio. Por otro lado, en el ECA CheckMate 025, no se observaron diferencias entre nivolumab y everolimus en la SG, calidad de vida y los EA, en la población total del estudio. Debido al similar perfil de seguridad de ambos medicamentos en observado en dicho ensayo, se podría esperar que nivolumab, al igual que everolimus frente a MTSP, también presente una mayor tasa de discontinuación por eventos adversos que MTSP. Así, con la evidencia disponible en la actualidad no es posible determinar un balance riesgo beneficio favorable para nivolumab, en comparación con la MTSP, en nuestra población de interés. Esto debido a no se ha podido demostrar que nivolumab ofrezca un beneficio en desenlaces clínicamente relevantes como la SG y la calidad de vida en la población de la pregunta PICO. Además, no se ha demostrado que nivolumab presente un mejor perfil de seguridad que la MTSP. Estos hallazgos impiden que una recomendación a favor del uso de nivolumab pueda ser respaldada técnicamente. Por lo expuesto, el Instituto de Evaluaciones de Tecnologías en Salud e Investigación - IETSI no aprueba el uso de nivolumab para el tratamiento de los pacientes con CCRcc avanzado, irresecable, con progresión a dos líneas de tratamiento con terapia anti-angiogénica.

Review of neovascular age-related macular degeneration treatment options.

Due to an aging population, visual impairment from neovascular age-related macular degeneration (nAMD) is increasing in the United States. Despite unprecedented improvements in vision preservation that patients can achieve with anti-vascular endothelial growth factor (VEGF) agents, innovations are needed to reduce the burden of intravitreal injections and improve outcomes in patients who do not respond adequately to currently available agents. The best present option for vision preservation is a "zero-tolerance for fluid" schedule of monitoring and intravitreal injections that patients may need to follow for many years. This treatment burden has resulted in patients not achieving optimal benefit or even falling through the cracks. This article reviews state-of-the-art management approaches including as-needed and treat-and-extend dosing regimens designed to reduce treatment burden.

Anticancer effect of berberine based on experimental animal models of various cancers: a systematic review and meta-analysis.

BACKGROUND: Numerous studies have explored the anti-tumor effect of berberine (BBR), but little clinical evidence guides the use of BBR in cancer patients. OBJECTIVES: Our aim was to investigate the impact of BBR on various cancers in healthy animals to promote the transformation from bench to bed. SEARCH METHODS: PubMed, Embase, Springer, and Cochrane databases were searched from January 2000 to October 2018 for relevant articles. SELECTION CRITERIA: Only published studies focusing on the relationship between BBR and various cancers in vivo were qualified. Two review authors independently assessed the risk of bias for each study, and any disagreement was resolved by discussion or by involving a third assessor. RESULTS: A total of 26 studies from 2000 to 2018, focusing on various cancer types, including breast cancer, liver cancer, colorectal cancer, nasopharyngeal carcinoma, lung cancer, gastric cancer, neuroepithelial cancer, endometrial carcinoma, esophageal cancer, tongue cancer, cholangiocarcinoma, and sarcoma were included. Overall, BBR reduced tumor volume (SMD =3.72, 95% CI: 2.89, 4.56, Z = 8.73, p < 0.00001) and tumor weight (SMD =2.35, 95% CI: 1.51, 3.19, Z = 5.50, p < 0.00001) in a linear The dose-response relationship (Pearson r = - 0.6717, p < 0.0001 in tumor volume analysis; Pearson r = - 0.7704, p < 0.0005 in tumor weight analysis). BBR inhibited angiogenesis in tumor tissues (SMD = 4.29, 95% CI: 2.14, 6.44, Z = 3.92, p < 0.00001), but it had no significant effect on the body weight of experimental animals (SMD = 0.11, 95% CI: - 0.70, 0.92, Z = 0.27, p = 0.78). Publication bias was not detected. CONCLUSION: BBR exerted anti-tumor effects in a variety of tumors in vivo, especially breast cancer and lung cancer, and the evidence was still insufficient in colorectal cancer and gastric cancer.

Nutraceuticals for the Treatment of Diabetic Retinopathy.

Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus and is characterized by degeneration of retinal neurons and neoangiogenesis, causing a severe threat to vision. Nowadays, the principal treatment options for DR are laser photocoagulation, vitreoretinal surgery, or intravitreal injection of drugs targeting vascular endothelial growth factor. However, these treatments only act at advanced stages of DR, have short term efficacy, and cause side effects. Treatment with nutraceuticals (foods providing medical or health benefits) at early stages of DR may represent a reasonable alternative to act upstream of the disease, preventing its progression. In particular, in vitro and in vivo studies have revealed that a variety of nutraceuticals have significant antioxidant and anti-inflammatory properties that may inhibit the early diabetes-driven molecular mechanisms that induce DR, reducing both the neural and vascular damage typical of DR. Although most studies are limited to animal models and there is the problem of low bioavailability for many nutraceuticals, the use of these compounds may represent a natural alternative method to standard DR treatments.

Repeated intravitreal injections of antivascular endothelial growth factor in patients with neovascular age-related macular degeneration may increase the risk of ischemic optic neuropathy.

BACKGROUND: Previous case reports have demonstrated the occurrence of ischemic optic neuropathy (ION) following intravitreal injections of antivascular endothelial growth factor (anti-VEGF). However, no previous studies have investigated the impact of injection numbers on the risk of ION. The aim of our study was to investigate whether repeated intravitreal injections of anti-VEGF would increase the risk of subsequent ION in patients with neovascular age-related macular degeneration (AMD). METHODS: A population-based, retrospective cohort study using the Taiwan National Health Insurance Research Database was conducted from 2007 to 2013. Neovascular AMD patients receiving intravitreal injections of anti-VEGF during the study period were enrolled in the study cohort. Enrollees were divided into three groups according to the categorized levels of injection number (first level: < 10 times, second level: 10-15 times, and third level: > 15 times). Kaplan-Meier curves were generated to compare the cumulative hazard of subsequent ION among the three groups. Cox regression analyses were used to estimate crude and adjusted hazard ratios (HRs) for ION development with respect to the different levels of injection numbers. The confounders included for adjustment were age, sex, and comorbidities (diabetes, hypertension, hyperlipidemia, ischemic heart disease, and glaucoma). RESULTS: In total, the study cohort included 77,210 patients. Of these, 26,520, 38,010, and 12,680 were in the first-, second-, and third-level groups, respectively. The Kaplan-Meier method revealed that the cumulative hazards of ION were significantly higher in those who had a higher injection number. After adjusting for confounders, the adjusted HRs for ION in the second- and third-level groups were 1.91 (95% confidence interval [CI], 1.32-2.76) and 2.20 (95% CI, 1.42-3.43), respectively, compared with those in the first-level group. CONCLUSIONS: Among patients with neovascular AMD, those who receive a higher number of anti-VEGF injections have a significantly higher risk of developing ION compared with individuals who receive a lower number of injections.

Anti-Angiogenic Activity of Curcumin in Cancer Therapy: A Narrative Review.

Curcumin is a naturally occurring polyphenol isolated from Curcuma longa that has various pharmacological activities, including, anti-inflammatory, anti-oxidant and anti-cancer properties. The anticancer effect of curcumin is attributed to activation of apoptotic pathways in cancer cells, as well as inhibition of inflammation and angiogenesis in the tumour microenvironment and suppression of tumour metastasis. Angiogenesis, which is the formation of new blood vessels from pre-existing ones, is a fundamental step in tumour growth and expansion. Several reports have demonstrated that curcumin inhibits angiogenesis in a wide variety of tumour cells through the modulation of various cell signaling pathways which involve transcription factors, protein kinases, growth factors and enzymes. This review provides an updated summary of the various pathways and molecular targets that are regulated by curcumin to elicit its anti-angiogenic activity.

Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study.

BACKGROUND: Regorafenib has proven activity in patients with pretreated gastrointestinal stromal tumours and colorectal and hepatocellular carcinoma. We designed REGOBONE to assess the efficacy and safety of regorafenib for patients with progressive metastatic osteosarcoma and other bone sarcomas. This trial comprised four parallel independent cohorts: osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma. In this Article, we report the results of the osteosarcoma cohort. METHODS: In this non-comparative, double-blind, placebo-controlled, phase 2 trial, patients aged 10 years or older with histologically confirmed osteosarcoma whose disease had progressed after treatment with one to two previous lines of chemotherapy for metastatic disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive either oral regorafenib (160 mg/day, for 21 of 28 days) or matching placebo. Patients in both groups also received best supportive care. Randomisation was done using a web-based system and was stratified (permuted block) by age at inclusion (<18 vs ≥18 years old). Investigators and patients were masked to treatment allocation. Patients in the placebo group, after centrally confirmed progressive disease, could cross over to receive regorafenib. The primary endpoint was the proportion of patients without disease progression at 8 weeks. Analyses were done by modified intention to treat (ie, patients without any major entry criteria violation who initiated masked study drug treatment were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02389244, and the results presented here are the final analysis of the osteosarcoma cohort (others cohorts are ongoing). FINDINGS: Between Oct 10, 2014, and April 4, 2017, 43 adult patients were enrolled from 13 French comprehensive cancer centres. All patients received at least one dose of assigned treatment and were evaluable for safety; five patients were excluded for major protocol violations (two in the placebo group and three in the regorafenib group), leaving 38 patients who were evaluable for efficacy (12 in the placebo group and 26 in the regorafenib group). 17 of 26 patients (65%; one-sided 95% CI 47%) in the regorafenib group were non-progressive at 8 weeks compared with no patients in the placebo group. Ten patients in the placebo group crossed over to receive open-label regorafenib after centrally confirmed disease progression. 13 treatment-related serious adverse events occurred in seven (24%) of 29 patients in the regorafenib group versus none of 14 patients in the placebo group. The most common grade 3 or worse treatment-related adverse events during the double-blind period of treatment included hypertension (in seven [24%] of 29 patients in the regorafenib group vs none in the placebo group), hand-foot skin reaction (three [10%] vs none), fatigue (three [10%] vs one [3%]), hypophosphataemia (three [10%] vs none), and chest pain (three [10%] vs none). No treatment-related deaths occurred. INTERPRETATION: Regorafenib demonstrated clinically meaningful antitumour activity in adult patients with recurrent, progressive, metastatic osteosarcoma after failure of conventional chemotherapy, with a positive effect on delaying disease progression. Regorafenib should be further evaluated in the setting of advanced disease as well as potentially earlier in the disease course for patients at high risk of relapse. Regorafenib might have an important therapeutic role as an agent complementary to standard cytotoxic chemotherapy in the therapeutic armamentarium against osteosarcoma. FUNDING: Bayer HealthCare.

Prevención de osteonecrosis asociada a medicamentos y ensayo clínico multicéntrico, Facultad de Odontología, Universidad de Buenos Aires / Prevention of drug-related osteonecrosis and multicentric clinical trial, School of Dentistry, University of Buenos Aires

La osteonecrosis asociada a medicamentos (ONAM) es un efecto adverso poco frecuente pero potencialmente serio que afecta a pacientes que reciben o recibieron tratamiento con drogas antirresortivas o antiangiogénicas. A partir de una revisión narrativa de la literatura, el presente artículo aporta conceptos básicos e información actualizada acerca de incidencia, factores de riesgo y prevención de ONAM desde la perspectiva de la Práctica Basada en la Evidencia. Además pone en conocimiento a la comunidad profesional de la Facultad de Odontología de la Universidad de Buenos Aires acerca de las actividades de investigación clínica llevadas a cabo en este área en la Cátedra de Cirugía y Traumatología Buco-Máxilo-Facial I de nuestra casa de estudios (AU)

Medicine related osteonecrosis of the jaws (MRONJ) is a rare but potentially serious side effect experienced by patients receiving treatment with antiresorptive or antiangiogenic drugs. Through a narrative review of the literature, this paper provides basic concepts and updated data about incidence, risk factors and prevention of MRONJ from the Evidence Based Practice perspective. It also informs the professional community of the School of Dentistry of the University of Buenos Aires about the clinical research activities carried out in this area in the Oral and Maxillofacial Surgery I Department (AU)

Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. METHODS: We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m2 on days 1-5) plus either oral sorafenib 400 mg or placebo twice daily on days 6-15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression. Investigators and patients were masked to allocation of sorafenib or placebo; topotecan treatment was open label. The primary endpoint was investigator-assessed progression-free survival, analysed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01047891. FINDINGS: Between Jan 18, 2010, and Sept 19, 2013, 185 patients were enrolled, 174 of whom were randomly assigned: 85 to sorafenib and 89 to placebo. Two patients in the sorafenib group had serious adverse events before treatment and were excluded from analyses. 83 patients in the sorafenib group and 89 in the placebo group started treatment. Progression-free survival was significantly improved with sorafenib versus placebo (hazard ratio 0·60, 95% CI 0·43-0·83; p=0·0018). Median progression-free survival was 6·7 months (95% CI 5·8-7·6) with sorafenib versus 4·4 months (3·7-5·0) with placebo. The most common grade 3-4 adverse events were leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]). Serious adverse events occurred in 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients. Of these, events were fatal in four patients (5%) in the sorafenib group (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) and seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia). Sorafenib was associated with increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%]). INTERPRETATION: Sorafenib, when given orally in combination with topotecan and continued as maintenance therapy, showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies. FUNDING: Bayer, Amgen, and GlaxoSmithKline.

Aortic Dissection and Cardiac Dysfunction Emerged Coincidentally During the Long-Term Treatment with Angiogenesis Inhibitors for Metastatic Renal Cell Carcinoma.

Angiogenesis inhibitors, such as sorafenib and axitinib, which target vascular endothelial growth factor (VEGF) signaling, are widely used for renal cell carcinoma, including metastasis. In this study, we report a case of cardiovascular adverse events of aortic dissection and cardiac dysfunction during treatment with sorafenib and axitinib for metastatic renal cell carcinoma. A 66-year-old man had been administered sorafenib for 2 years after nephrectomy due to renal cell carcinoma. To control the progression of metastatic lung tumor, axitinib was started after sorafenib for four years. During the treatment, angiotensin II type 1 receptor blockers and Ca antagonists were used to strictly control the axitinib-induced hypertension and proteinuria. Aortic dissection and cardiac dysfunction occurred coincidentally. Considering the critical role of VEGF signaling in the homeostasis of the cardiovascular system, we speculated that the long-term use of axitinib and sorafenib directly influenced the initiation of aortic dissection and cardiac dysfunction. Although the precise mechanisms underlying the aortic dissection and cardiac dysfunction induced by angiogenesis inhibition are still elusive, onco-cardiologists and oncologists should pay careful attention to cardiovascular toxicity and complications in patients with cancer, particularly patients undergoing long-term cancer treatment.

Safety and Efficacy of Anlotinib, a Multikinase Angiogenesis Inhibitor, in Patients with Refractory Metastatic Soft-Tissue Sarcoma.

Purpose: The prognosis for patients with refractory soft-tissue sarcoma (STS) is dismal. Anlotinib has previously shown antitumor activity on STS in preclinical and phase I studies.Patients and Methods: Patients 18 years and older, progressing after anthracycline-based chemotherapy, naïve from angiogenesis inhibitors, with at least one measurable lesion according to RECIST 1.1, were enrolled. The main subtypes eligible were undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), and clear cell sarcoma (CCS). Participants were treated with anlotinib. The primary endpoint was progression-free rate at 12 weeks (PFR12 weeks).Results: A total of 166 patients were included in the final analysis. Overall, the PFR12 weeks was 68%, and objective response rate was 13% (95% confidence interval, 7.6%-18%). The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 12 months, respectively. The PFR12 weeks, median PFS and OS were: 58%, 4.1 and 11 months for UPS (n = 19); 63%, 5.6 and 13 months for LPS (n = 13); 75%, 11 and 15 months for LMS (n = 26); 75%, 7.7 and 12 months for SS (n = 47); 81%, 5.6 and 12 months for FS (n = 18); 77%, 21 and not reached for ASPS (n = 13); 54%, 11 and 16 months for CCS (n = 7); and 44%, 2.8 and 8.8 months for other sarcoma (n = 23), respectively. The most common clinically significant grade 3 or higher adverse events were hypertension (4.8%), triglyceride elevation (3.6%), and pneumothorax (2.4%). No treatment-related death occurred.Conclusions: Anlotinib showed antitumor activity in several STS entities. The toxicity was manageable. Clin Cancer Res; 24(21); 5233-8. ©2018 AACR.