One-year outcomes and safety assessment of faricimab in treatment-naïve patients with neovascular age-related macular degeneration in Japan.

This multicentre retrospective study evaluated the 1-year outcomes and safety profile of faricimab in treatment-naïve patients with neovascular age-related macular degeneration (nAMD). Fifty-five patients (57 eyes) underwent loading therapy comprising three monthly faricimab injections. If dryness was achieved by the third month, subsequent treat-and-extend (TAE) follow-up continued at a minimum 8-week interval thereafter. If wet macula persisted at the third month, a fourth dose was administered, followed by the TAE regimen. After 1 year, improvements in visual acuity (0.44 ± 0.46 [baseline] to 0.34 ± 0.48; p < 0.01) and central foveal thickness (326 ± 149 [baseline] to 195 ± 82 µm; p < 0.0001) were significant. Dry macula, characterised by the absence of intraretinal or subretinal fluid, was achieved in 65% of cases. Treatment intervals varied, ranging from 8 to 16 weeks, with 44% of eyes extending to a 16-week interval, followed by 33% at 8 weeks, 16% at 12 weeks, 5% at 14 weeks, and 2% at 10 weeks. Notably, 50% of the polypoidal choroidal vasculopathy patients exhibited complete regression of polypoidal lesions between 12 and 15 months. Faricimab treatment in nAMD patients induced significant improvements in central vision and retinal morphology. Two cases of retinal pigment epithelial tears and one case of iritis were reported as ocular complications.

[Application of optical coherence tomography in the assessment of the posterior lens capsule during anti-angiogenic therapy]. / Primenenie opticheskoi kogerentnoi tomografii v otsenke zadnei kapsuly khrustalika na fone provedeniya antiangiogennoi terapii.

Intravitreal injection (IVI) of anti-angiogenic drugs is one of the most common therapeutic procedures in ophthalmology. In recent years, a new non-contact study method has been developed - anterior segment optical coherence tomography (AS-OCT), which allows the formation of three-dimensional images of the lens and provides more detailed information about its structure and morphology. PURPOSE: This study uses optical coherence tomography method to analyze the risks of developing changes in the posterior lens capsule in patients after IVI of an anti-angiogenic drug. MATERIAL AND METHODS: The study involved 100 people (14 men and 86 women) with a natural lens and neovascular age-related macular degeneration (nAMD). The average age was 70.57±7.98 years. During the study (12 months), all patients underwent IVI of an anti-angiogenic drug aflibercept in the treat-and-extend (T&E) mode. All subjects were divided into 2 groups: with a total number of IVI less than 10 - group 1 (50 patients), and more than 10 IVI - group 2 (50 patients, of which 49 were included in the study). All patients underwent OCT using the Optopol REVO NX device (Poland) with the Anterior B-scan Wide protocol before inclusion in the study, as well as after 3, 6 and 12 months. RESULTS: It was found that the risk of developing a posterior lens capsule rupture, visualized using OCT, depends on the total number of IVI (correlation coefficient 0.473 p=0.001): the more IVI, the higher the probability that damage to the posterior capsule will occur after the next IVI, and after the 15th injection the risk of developing damage to the posterior capsule increases sharply. CONCLUSION: The astudy analyzed the risk factors for the development of posterior lens capsule damage that can be detected using OCT, and presented three risk groups for the development of rupture (or damage) of the posterior lens capsule depending on the number of intravitreal injections performed.

[Relationship between treatment and cost with visual acuity improvement in age-related macular degeneration]. / Relación del tratamiento y coste con la ganancia de agudeza visual en la degeneración macular asociada a la edad

BACKGROUND: We examined the relationship between visual acuity changes (VA) and the cost of care and treatment with anti-vascular endothelial growth factors (antiVEGF) in patients diagnosed with age-related exudative macular degeneration (exudative AMD). METHODS: Observational, longitudinal, retrospective study of patients ≥50 years of age diagnosed with exudative AMD, with a log-MAR VA between 0.6 and 0.06. and 0.06. Follow-up and treatment were done in our tertiary hospital between January 1, 2014 and December 31, 2018. RESULTS: The study included 778 patients; 62.2% female and mean age 79.83±7.94 years; 957 eyes had exudative AMD. Mean of final VA (0.65±0.45) increasing 3.2% compared to initial values. Ranibizumab was administered to 60.3% of the eyes, aflibercept to 10.2% and ranibizumab + aflibercept (mixed group) to 29.5%. Significant increase in VA was seen in the group with the mixed treatment, with no inter-group differences. Although follow-up/treatment was longer for the mixed group, they received fewer anti-VEGF injections and optical coherence tomography (OCT). The total expenditure per year and treated eye was € 1,972.7±824.5; costs were higher for visit, OCT, and treatment in the aflibercept group, and lower for fluorescein angiography, antiVEGF treatment, and total costs in the mixed group. Decimal VA gain had a cost of € 872±1,077.7 with no significant inter-group differences. CONCLUSIONS: AntiVEGF treatments (ranibizumab, aflibercept, or both) maintained VA in patients with exudative AMD. Overall, care and treatment costs were lower in the group that received both drugs.

Cardiovascular toxicity of angiogenesis inhibitors and immune checkpoint inhibitors: synergistic anti-tumour effects at the cost of increased cardiovascular risk?

In the past two decades, treatment outcomes for a wide range of malignancies have improved remarkably due to the development of novel anti-cancer therapies, including vascular endothelial growth factor inhibitors (VEGFIs) and immune checkpoint inhibitors (ICIs). Despite their unprecedented anti-tumour effects, it is becoming increasingly clear that both types of agents are associated with specific cardiovascular toxicity, including hypertension, congestive heart failure, myocarditis and acceleration of atherosclerosis. Currently, VEGFI and ICI combination therapy is recommended for the treatment of advanced renal cell carcinoma (RCC) and has shown promising treatment efficacy in other tumour types as well. Consequently, VEGFI and ICI combination therapy will most likely become an important therapeutic strategy for various malignancies. However, this combinatory approach is expected to be accompanied by a substantial increase in cardiovascular risk, as both types of agents could act synergistically to induce cardiovascular sequelae. Therefore, a comprehensive baseline assessment and adequate monitoring by specialised cardio-oncology teams is essential in case these agents are used in combination, particularly in high-risk patients. This review summarises the mechanisms of action and treatment indications for currently registered VEGFIs and ICIs, and discusses their main vascular and cardiac toxicity. Subsequently, we provide the biological rationales for the observed promising synergistic anti-tumour effects of combined VEGFI/ICI administration. Lastly, we speculate on the increased risk for cardiovascular toxicity in case these agents are used in combination and its implications and future directions for the clinical situation.

Assessment of extended urine protein monitoring frequency in patients receiving bevacizumab.

PURPOSE: Proteinuria monitoring is required for patients receiving bevacizumab. Nonetheless, the frequency of monitoring is not specified in the package insert. A 2014 quality improvement study performed at Yale New Haven Health System (YNHHS) found that proteinuria occurred in 15% (all grade) of the 162 patients evaluated. These results led to decreasing the frequency of proteinuria monitoring from every treatment to every other treatment. The objective of this study is to assess the safety of the extended interval for urine protein (UP) monitoring. METHODS: Patients receiving at least four bevacizumab treatments at YNHHS from January to June 2017 were randomly selected and retrospectively reviewed. The following data were collected: baseline patient characteristics, comorbidities, medication history, and proteinuria monitoring. The grade, prevalence and management of proteinuria were evaluated. The minimum necessary sample size was determined to be 384 treatments to achieve a 95% confidence interval. RESULTS: Fifty-five patients and 388 bevacizumab treatments were evaluated. Urine protein was assessed in 52.5% of treatments. The incidence of proteinuria among patients was 7.2% (grade 2) and 0% (grade 3). Cumulative dose and the number of total bevacizumab doses did not affect the timing for onset or severity of proteinuria. Two patients with UP ≥ 2+ were further monitored using a 24-h urine collection test with negative results. No treatments were held due to proteinuria. CONCLUSION: Monitoring proteinuria every other treatment does not increase the frequency of adverse events. Urine protein is now monitored prior to every third bevacizumab treatment, reducing unnecessary labs and chair time.

Movement of Poly-ADP Ribose (PARP) Inhibition into Frontline Treatment of Ovarian Cancer.

The use of poly (ADP-ribose) polymerase (PARP) inhibitors in the front-line management of advanced ovarian cancer has recently emerged as an exciting strategy with the potential to improve outcomes for patients with advanced ovarian cancer. In this article, we review the results of four recently published Phase III randomised controlled trials evaluating the use of PARP inhibitors in the primary treatment of ovarian cancer (SOLO1, PRIMA, PAOLA-1, and VELIA). Collectively, the studies suggest that PARP maintenance in the upfront setting is most beneficial among patients with BRCA-associated ovarian cancers (hazard ratios range from 0.31 to 0.44), followed by patients with tumours that harbour homologous recombination deficiencies (hazard ratios range from 0.33 to 0.57). All three studies that included an all-comer population were able to demonstrate benefit of PARP inhibitors, regardless of biomarker status. The FDA has approved olaparib for front-line maintenance therapy among patients with BRCA-associated ovarian cancers, and niraparib for all patients, regardless of biomarker status. In determining which patients should be offered front-line maintenance PARP inhibitors, and which agent to use, there are multiple factors to consider, including FDA indication, dosing preference, toxicity, risks versus benefits for each patient population, and cost. There are ongoing studies further exploring the front-line use of PARP inhibitors, including the potential downstream effects of PARP-inhibitor resistance in the recurrent setting, combining PARP-inhibitors with other anti-angiogenic drugs, immunotherapeutic agents, and inhibitors of pathways implicated in PARP inhibitor resistance.

Cost-effectiveness of Intravitreal Ranibizumab With Verteporfin Photodynamic Therapy Compared With Ranibizumab Monotherapy for Patients With Polypoidal Choroidal Vasculopathy.

Importance: The EVEREST II trial showed that for patients with polypoidal choroidal vasculopathy (PCV), intravitreal ranibizumab in combination with verteporfin photodynamic therapy improves visual acuity relative to ranibizumab monotherapy. However, whether combination therapy is incrementally cost-effective relative to monotherapy during a lifetime is unclear. Objective: To assess the incremental cost-effectiveness of combination therapy compared with ranibizumab monotherapy in patients with PCV. Design, Setting, and Participants: This model-based, economic evaluation used 2018 unit cost data from a tertiary eye hospital in Singapore, first- and second-year outcomes and resource use data from a multicenter trial across various Asian countries (EVEREST II) to model a hypothetical cohort of patients with symptomatic PCV. Scenario analyses and deterministic and probabilistic sensitivity analyses were performed to examine uncertainty. Data were collected from October 2018 through April 2019 and analyzed from March through October 2019. Interventions: This model used data from the EVEREST II trial, in which all participants were given 0.5 mg of intravitreal ranibizumab once every 4 weeks for the first 3 months. Subsequent administration occurred as needed. For participants receiving combination therapy, standard fluence (50 J/cm3) photodynamic therapy with 6-mg/m2 verteporfin was administered once during the first 3 months and thereafter as needed. Main Outcomes and Measures: Incremental cost per quality-adjusted life-year (QALY) gained for combination therapy relative to monotherapy for patients with PCV. Results: In this model based on a cohort of 1000 patients aged 68 years, a patient with PCV incurred a total cost in Singapore dollars (SGD) of 92 327 (US $67 399) with combination therapy and SGD 92 371 (US $67 431) with monotherapy during a lifetime horizon, generating a modest cost savings of SGD 44 (US $32) per patient undergoing combination therapy. Lifetime QALYs were estimated to be 7.87 for combination therapy and 7.85 for monotherapy, for an incremental gain of 0.02 QALYs. Combination therapy remained cost-saving or cost-effective in all lifetime scenarios modeled, but during shorter time horizons and at lower monotherapy costs, it may not be cost-effective. Conclusions and Relevance: This study found combination therapy to be a dominant (more effective and less costly) strategy, being similar in costs and slightly more effective than ranibizumab monotherapy during a lifetime horizon. However, decreasing the time horizon to less than 10 years and/or reductions in the cost of monotherapy may result in combination therapy no longer being cost-effective.

Cardiovascular assessment after treatment for retinopathy of prematurity: a comparative study between anti-VEGF agent (aflibercept) and laser.

OBJECTIVE: The aim of this study was to compare the cardiac effects and aortic arterial indices following intravitreal aflibercept treatment or diode laser photocoagulation for the treatment of retinopathy of prematurity (ROP) in infants. METHODS: This single-centre, retrospective study was conducted in infants who were administered laser photocoagulation (LPC) or intravitreal aflibercept (IVA) treatment as initial treatment and had completed at least one year of corrected age. The patients were evaluated in terms of aortic elastic parameters, right and left ventricular systolic and diastolic function using conventional, pulsed Doppler and tissue Doppler imaging (TDI) echocardiographic parameters. RESULTS: Fifteen infants were in the LPC group, 16 in the IVA group, and 20 in the control group. Although there were some statistically significant differences in terms of pulsed and TDI echocardiographic parameters between the treatment and control groups, these values could not clearly be adopted as a diastolic dysfunction and myocardial performance indices were not influenced. The aortic elastic parameters were impaired in both LPC and IVA groups compared to the control group. Consequently, we observed only minor differences between the treatment groups, which may suggest subtle changes due to the anti-angiogenic treatment. CONCLUSIONS: Although favourable and promising outcomes were obtained with intravitreal injection of anti-vascular endothelial growth factor agents for the treatment of ROP, concerns have been raised about potential systemic side effects, including potential cardiovascular side effects caused by these agents. The small reduction in right ventricular Doppler velocities could probably be explained by the use of anti-angiogenic or laser treatment in infants.

The tale of lenalidomide clinical superiority over thalidomide and regulatory and cost-effectiveness issues.

In April 2017, the National Sanitary Surveillance Agency (ANVISA-Brazil) approved lenalidomide (LEN) for multiple myeloma (MM) and myelodysplastic syndrome. ANVISA had rejected the first application in 2010, and denied a request for reconsideration in 2012. The reason for rejection was the lack of comparative effectiveness studies proving that LEN was more effective than thalidomide (THAL), a strictly controlled drug regulated by Federal law 10.651/2003 and dispensed to patients (at no costs) through public health system units and hospitals. ANVISA unexplained retreat on the LEN approval for marketing was an unquestionable triumph of the lobbying that ensued the denial, at the forefront of which were politicians, Congress members, patient organizations and medical societies. Two randomized (phase III) trials and three observational (case-control and population-based cohort) compared the effectiveness of THAL- versus LEN-based therapies in MM. Overall, these studies showed no difference in efficacy between LEN- and THAL-based therapies. LEN caused less neuropathy, and more severe hematologic adverse effects. It is much costlier than THAL, and substitution of THAL by LEN shall raise considerably public healthcare costs in Brazil.

The tale of lenalidomide clinical superiority over thalidomide and regulatory and cost-effectiveness issues / A narrativa de que a lenalidomida é clinicamente superior à talidomida, e questões regulatórias e de custo-efetividade

Abstract In April 2017, the National Sanitary Surveillance Agency (ANVISA-Brazil) approved lenalidomide (LEN) for multiple myeloma (MM) and myelodysplastic syndrome. ANVISA had rejected the first application in 2010, and denied a request for reconsideration in 2012. The reason for rejection was the lack of comparative effectiveness studies proving that LEN was more effective than thalidomide (THAL), a strictly controlled drug regulated by Federal law 10.651/2003 and dispensed to patients (at no costs) through public health system units and hospitals. ANVISA unexplained retreat on the LEN approval for marketing was an unquestionable triumph of the lobbying that ensued the denial, at the forefront of which were politicians, Congress members, patient organizations and medical societies. Two randomized (phase III) trials and three observational (case-control and population-based cohort) compared the effectiveness of THAL- versus LEN-based therapies in MM. Overall, these studies showed no difference in efficacy between LEN- and THAL-based therapies. LEN caused less neuropathy, and more severe hematologic adverse effects. It is much costlier than THAL, and substitution of THAL by LEN shall raise considerably public healthcare costs in Brazil.

Resumo A Agência Nacional de Vigilância Sanitária (ANVISA) aprovou em abril de 2017 a lenalidomida (LEN) para o mieloma múltiplo (MM) e síndrome mielodisplásica. A ANVISA havia negado o registro em 2010, e indeferido um recurso apresentado em 2012. O motivo do indeferimento foi a falta de estudos comparativos de efetividade demonstrando que LEN era mais eficaz do que a talidomida (TAL), um medicamento rigorosamente controlado pela lei federal 10.651/2003 e dispensado gratuitamente a pacientes através de unidades de saúde e hospitais públicos. O recuo não explicado da ANVISA em relação ao registro da LEN foi um inquestionável triunfo do lobby que sucedeu a recusa inicial do registro, a frente do qual estavam políticos, membros do Congresso, associações de pacientes e sociedades médicas. Dois ensaios randomizados (fase III) e três estudos observacionais (caso-controle e coorte de base populacional) compararam a efetividade de terapias para o MM com TAL- e com LEN. Em conjunto, esses estudos mostraram que não havia diferenças quanto a eficácia de tratamentos com LEN- e aqueles com TAL. A LEN causou menos neuropatias, e efeitos adversos hematológicos mais graves. Ela é muito mais cara do que a TAL, e a substituição da TAL pela LEN aumentará muito os custos da assistência pública à saúde no Brasil.

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.

Off-label use of bevacizumab in the treatment of retinal disease: ethical implications.

Anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionised the treatment of a variety of ophthalmic conditions and has become the first-line therapy for a range of retinal diseases. Bevacizumab, a VEGF inhibitor first approved for the treatment of colorectal cancer, has been shown to be nearly or virtually as effective and safe as other anti-VEGF therapies in the treatment of certain retinal diseases but is not approved or registered by the Food and Drug Administration or European Medicines Agency. While other anti-VEGF options are approved and registered, they are generally more expensive and less accessible. Accordingly, despite its off-label status, bevacizumab is frequently used for a variety of disabling retinal diseases. Indeed, bevacizumab is included on the World Health Organization's list of essential medicines. However, its use in some parts of the world remains restricted due to its off-label status. How, then, should healthcare authorities approach this situation? What are the ethical and societal implications of adhering to a standard and generally effective evaluation and approval system while restricting access to a potentially cost-saving therapy? In countries where its use is not restricted, how should providers approach off-label treatment with bevacizumab? By examining the evidence behind bevacizumab's efficacy and safety and evaluating the individual and societal implications of off-label use and restriction, this paper illustrates the ethical factors providers and policy makers must consider in the off-label use of bevacizumab and ultimately argues for increased access to bevacizumab in the treatment of retinal disease.

Assessment of the Antiangiogenic and Anti-Inflammatory Properties of a Maslinic Acid Derivative and its Potentiation using Zinc Chloride.

Maslinic acid is a pentacyclic triterpene with a plethora of biological activities, including anti-inflammatory, antioxidant, antimicrobial, cardioprotective, and antitumor effects. New derivatives with improved properties and broad-spectrum activity can be obtained following structural changes of the compound. The present study was aimed to characterize a benzylamide derivative of maslinic acid-benzyl (2α, 3ß) 2,3-diacetoxy-olean-12-en-28-amide (EM2)-with respect to the anti-angiogenic and anti-inflammatory effects in two in vivo experimental models. Consequently, the compound showed good tolerability and lack of irritation in the chorioallantoic membrane assay with no impairment of the normal angiogenic process during the tested stages of development. In the acute ear inflammation murine model, application of EM2 induced a mild anti-inflammatory effect that was potentiated by the association with zinc chloride (ZnCl2). A decrease in dermal thickness of mice ears was observed when EM2 and ZnCl2 were applied separately or in combination. Moreover, hyalinization of the dermis appeared only when EM2 was associated with ZnCl2, strongly suggesting the role of their combination in wound healing.

Safety and Efficacy of Anti-Vascular Endothelial Growth Factor Therapies for Neovascular Age-Related Macular Degeneration: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the evidence on the safety and efficacy of anti-vascular endothelial growth factor (VEGF) therapies for the treatment of neovascular age-related macular degeneration (AMD). METHODS: A literature search of the PubMed and Cochrane Library databases was last conducted in February 2017; there were no date restrictions, and the search was limited to studies published in English. The combined searches yielded 191 citations, 28 of which were selected because they were clinical trials and were deemed clinically relevant for the Ophthalmic Technology Assessment Committee Retina/Vitreous Panel to review in full. The panel methodologist then assigned a level of evidence rating to each study. RESULTS: Sixteen of the 28 citations provided level I evidence supporting the use of anti-VEGF agents for neovascular AMD, including intravitreal ranibizumab, aflibercept, and bevacizumab. Eight studies reviewed provided level II evidence, and 4 studies provided level III evidence, but only the level I studies are included in this assessment. There are long-term follow-up data on the efficacy of ranibizumab and bevacizumab (≥5 years), but these data are subject to the bias of incomplete follow-up. CONCLUSIONS: Review of the literature indicates that intravitreal injection of anti-VEGF therapy is safe and effective for neovascular AMD over 2 years, the period for which data are available. Further research is needed to evaluate the long-term safety and comparative efficacy of these agents.

Bone metastases and age are associated with earlier dose reductions in metastatic clear-cell renal cell carcinoma patients treated with angiogenesis inhibitors.

Background: Metastatic clear-cell renal cell carcinoma (m-ccRCC) patients with bone metastases (BM) treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) have a poorer outcome compared to patients without BM. We aimed to investigate whether an increased incidence of VEGFR-TKI treatment interruptions and/or dose reductions in patients with BM could explain this difference in outcome. Patients and methods: Retrospective study on m-ccRCC patients treated in first-line with VEGFR-TKI. Analysis of the incidence of treatment interruptions and dose reductions and time-to-event analysis. Study of the correlation with the presence of BM at start of first-line VEGFR-TKIs. Results: Two-hundred-and-five patients were included. In patients with BM, median time-to-dose-reduction was significantly shorter (3 versus 5 cycles; p = 0.005) than in patients without BM. 63% of the total number of cycles was administered at reduced dose, compared to 41% in patients without BM. Age at start of VEGFR-TKI (≤ versus >70 years) was significantly associated with median time-to-dose-reduction (5 versus 3 cycles; p = 0.007). On multivariate analysis, the presence of BM (p = 0.004; HR 1.82, 95%CI 1.21-2.73) and age at start of VEGFR-TKIs (p = 0.017; HR 1.65, 95%CI 1.10-2.50) were independently associated with time-to-dose-reduction. Conclusion: In m-ccRCC patients treated with VEGFR-TKIs, dose reductions occurred earlier in patients with BM compared to patients without BM and in elderly patients.

Evaluation of Physician Knowledge of the Key Safety Information for Aflibercept in Canada: Evaluation of Risk-Minimization Measures.

BACKGROUND: As part of the risk-management plan (RMP) for aflibercept, materials have been developed to educate physicians in Canada on the key safety information and safe use for aflibercept. OBJECTIVE: The objectives of this study were to assess whether physicians in Canada received and reviewed the aflibercept educational materials (i.e. vial preparation instruction card, intravitreal injection procedure video, and product monograph) and to evaluate their knowledge of key safety information. METHODS: Retinal specialists and ophthalmologists who prescribe and/or administer aflibercept were recruited to complete a survey. Physicians could complete and return a paper questionnaire by mail or complete the questionnaire online via a study website. RESULTS: Of the 308 physicians invited to participate in the survey, 95 (31%) completed the questionnaire. Nearly all physicians (98%) reported receiving at least one of the educational materials. The proportion of correct responses to individual questions on storage and preparation of aflibercept ranged from 54 to 98%. Physician knowledge was high on the recommended dose of aflibercept (91%), dose preparation (91-96% on individual items), and dosing guidelines (75-95% on individual items). Most physicians knew the contraindications for aflibercept (89%) and that aflibercept should not be used in pregnancy unless clearly indicated by medical need in which benefits outweigh risks (60%); 21% responded more conservatively that aflibercept should never be used in pregnancy. Knowledge was high for most questions about injection procedures (91-99% on individual items); however, fewer physicians (24%) correctly reported that the eye should be covered with a sterile drape. Knowledge was high for possible side effects (89-100% on individual items) and actions to take in relation to the potential for increased intraocular pressure (86-93% on individual items). CONCLUSION: Nearly all physicians (98%) reported having received the product monograph, and most (82%) reported having received the vial preparation instruction card; nearly half (46%) reported having received the intravitreal injection procedure video. Physicians' knowledge of the most important topics was high. Knowledge varied for topics that are less frequently encountered (e.g. use in women of childbearing potential) and for recommendations that are not standard medical practice in Canada (e.g. use of sterile drape).

Assessment of the risk of antiangiogenic agents before and after surgery.

Angiogenesis plays a critical role in the growth, progression, and metastasis of numerous solid tumor types, and thus, antiangiogenic agents have been studied for many years as potential therapeutic agents. Many different antiangiogenic agents, including monoclonal antibodies and multi-targeted tyrosine kinase inhibitors (TKIs), have been approved for various oncology indications, and promising clinical activity has been demonstrated. However, some of these agents have also been associated with serious safety concerns. Because angiogenesis is an important step in the wound healing process, agents targeting the angiogenesis pathway may interfere with wound healing, thus increasing the risk of surgical wound complications, such as dehiscence, surgical site bleeding, and wound infection. Nevertheless, antiangiogenic agents can be safely used in the perioperative setting if oncologists and surgeons are educated on the biology and pharmacokinetics of these agents. This review discusses the available published literature regarding surgical complications associated with the use of antiangiogenic agents and provides updated clinical recommendations on the optimal timing between surgery and antiangiogenic therapy. Due to the paucity of data surrounding this topic, current and future clinical trials need to evaluate prospectively the potential risks for surgical complications associated with antiangiogenic therapies to establish specific guidelines for their safe and effective use within the surgical oncology community.

Aflibercept, bevacizumab or ranibizumab for diabetic macular oedema: recent clinically relevant findings from DRCR.net Protocol T.

PURPOSE OF REVIEW: The aim of this study was to provide clinically relevant findings from the DRCR.net Protocol T, a multicentre randomized clinical trial comparing intravitreous aflibercept, repackaged (compounded) bevacizumab and ranibizumab for vision-impairing centre-involved diabetic macular oedema (DME). RECENT FINDINGS: At 1 year, all three antivascular endothelial growth factor (anti-VEGF) drugs, on average, improved visual acuity. There was no difference among drugs in mean change in visual acuity from baseline among eyes with baseline Snellen equivalent visual acuity of 20/32 to 20/40, whereas aflibercept yielded superior vision outcomes among eyes with baseline visual acuity of 20/50 to 20/320. At 2 years, aflibercept remained superior, on average, to bevacizumab, but not ranibizumab, among eyes with baseline visual acuity of 20/50 to 20/320. Over 2 years, in post-hoc area-under-the-curve analysis, aflibercept vision outcomes were superior to bevacizumab or ranibizumab among these eyes. All three drugs had comparable ocular and systemic safety profiles. The substantial cost differential between aflibercept and bevacizumab raises challenges when safety and efficacy are at odds with cost-effectiveness results. SUMMARY: When initial visual acuity loss is mild, there are no apparent differences, on average, among aflibercept, bevacizumab and ranibizumab for treating DME. When visual acuity loss is moderate or worse, aflibercept is more likely to improve visual acuity.

A Prospective Observational Study for Assessment and Outcome Association of Circulating Endothelial Cells in Clear Cell Renal Cell Carcinoma Patients Who Show Initial Benefit from First-line Treatment. The CIRCLES (CIRCuLating Endothelial cellS) Study (SOGUG-CEC-2011-01).

BACKGROUND: Markers able to predict the response to antiangiogenics in metastatic clear cell renal cell carcinoma (ccRCC) are not available. The development of new treatment options like immunotherapy are reaching the clinic; therefore, predictors of benefit from these different available treatments are increasingly needed. OBJECTIVE: In this study, we prospectively assessed the association of circulating endothelial cells (CECs) in peripheral blood with long-term benefit from first-line treatment in ccRCC. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational study was designed involving 13 institutions of the Spanish Oncology Genitourinary Group. Adult patients diagnosed with advanced ccRCC who had achieved response or disease stabilization after 3 mo on first-line therapy were eligible. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: CECs were isolated from peripheral blood, captured with ferrofluids coated with monoclonal antibodies directed against the CD146 antigen, and assessed centrally with an automated standardized system. CECs were defined as 4',6-diamidino-2-phenylindole+, CD105+, and CD45-. Blood samples were systematically taken every 6 wk for 15 mo or until tumor progression, whichever occurred first. Clinical data were externally monitored at all centers. RESULTS AND LIMITATIONS: From August 9, 2011, to January 17, 2013, 75 patients were enrolled in the study. Patients with baseline CECs above the median showed a significantly longer progression-free survival than those with low CECs (22.2 mo vs 12.2 mo) with a hazard ratio of 2.5 (95% confidence interval: 1.2-5.3, p=0.016). There was no difference between CEC levels at baseline and at tumor progression (medians of 50 CECs/4ml and 52 CECs/4ml, respectively). CONCLUSIONS: Under antiangiogenic treatment, the detection of higher CEC levels is associated with clinical benefit in terms of progression-free survival in ccRCC. PATIENT SUMMARY: Antiangiogenics are the cornerstone of treatment in kidney cancer. Since they target endothelial rather than tumor cells, we studied the correlation between levels of circulating endothelial cells in peripheral blood and long-term benefit in patients on antiangiogenic therapy. Higher levels were associated with long-term benefit, suggesting that this determination could help to separate best responders from those who could require a more intensive approach.

Anti-Angiogenic Tyrosine Kinase Inhibitors and Reversible Posterior Leukoencephalopathy Syndrome: Could Hypomagnesaemia Be the Trigger?

Reversible posterior leukoencephalopathy syndrome (RPLS), also known frequently as posterior reversible encephalopathy syndrome (PRES), is a characteristic acute neuro-radiology syndrome with clinical presentation that typically includes acute hypertension, seizures and other neurological symptoms and signs. Many patients with RPLS have (a history of) pre-existing hypertension and in receipt of diuretics. It is being diagnosed more frequently and in association with an increasing number of morbidities and medications. Drugs most frequently implicated are immunosuppressant drugs and anticancer agents, including a number of anti-angiogenic tyrosine kinase inhibitors (TKIs). Hypomagnesaemia is a frequent finding at presentation in RPLS patients, which is known to lead to or aggravate hypertension. Pre-eclampsia, a variant of RPLS, responds effectively to intravenous magnesium. Cyclosporin, tacrolimus and some TKIs that induce RPLS are also known to give rise to both hypertension and hypomagnesaemia. This raises an interesting hypothesis that hypomagnesaemia may play a contributory role in triggering RPLS in some patients by acutely raising the blood pressure further. Additional systematic studies are required to test this hypothesis. If the hypothesis is confirmed, hypomagnesaemia offers an effective target for risk mitigation and prevention of RPLS in patients identified at risk.