In Vitro Assessment of the Cytotoxic Effect of 5-Fluorouracil, Thymoquinone and their Combination on Tongue Squamous Cell Carcinoma Cell Line.

BACKGROUND: Tongue cancer is the most prevalent type of oral cancer. Recently, natural compounds have been considered important resources for several anticancer drugs. Thymoquinone (TQ) exhibits a potent anti-cancer effect. 5-Fluorouracil (5-FU) is a chemotherapeutic drug that has been utilized in the treatment of cancer. Recently, combination therapy has gained popularity as a treatment option for patients with cancer. OBJECTIVES: The present study was carried out to assess the cytotoxic effect of 5-Fluorouracil (5-FU), Thymoquinone (TQ), and their combination on tongue squamous cell carcinoma cell line (HNO-97). METHODS: Tongue carcinoma cell line (HNO-97) was maintained in cultured flasks and the cells were divided into four groups; group Ι: control untreated group, group ΙΙ: HNO-97-treated cells with different concentrations of 5-FU from 0.5 µM/ml to 3µM/ml, group ΙIΙ: HNO-97-treated cells with different concentrations of TQ from 7.25µM/ml to 23.05µM/ml, and group ΙV: HNO-97-treated cells with both 5-FU and TQ in serial concentrations  till (IC50) in a dose of 27.44 µM/ml. Determination of the cytotoxic effect of the tested agents on the HNO-97 cell line was done using methyl thiazole tetrazolium assay, nuclear morphometric analysis, microscopic examination, and annexin-v/ propidium iodide staining assay. RESULT: The findings revealed that the cytotoxic effect of 5-FU, TQ, and their combination on tongue squamous cell carcinoma cell line (HNO-97) was dose-dependent. The microscopic examination revealed that 5-FU, TQ alone, or their combination induced apoptotic cell death. P-value < 0.05 was statistically significant. CONCLUSION: The combination of 5-FU and TQ produced a marked cytotoxic effect on HNO-97 cells.

Efficacy, safety and cost-effectiveness of 5-fluorouracil versus interferon α-2b as adjuvant therapy after surgery in ocular surface squamous neoplasia in a southern European tertiary hospital.

PURPOSE: To analyze the efficacy, safety and cost-effectiveness of adjuvant therapy with 5-fluorouracil (5-FU) compared to interferon α-2b (IFNα-2b) after surgery in ocular surface squamous neoplasia (OSSN). METHODS: Retrospective study that included patients diagnosed with OSSN, who underwent surgical excision followed by adjuvant therapy with IFN α-2b (Group A) or 5-FU (Group B), in a tertial referral hospital. Clinical data collected included: demographics, risk factors, appearance, size and location of the lesions, slit-lamp examination, anterior segment optical coherence tomography, iconography and histological classification of subtypes of OSSN. Costs derived from surgery and adjuvant therapy were noted. Resolution of the lesion, recurrences and adverse events were studied. Cost-effectiveness analysis was performed with the incremental cost-effectiveness index (CEI). RESULTS: 54 cases of 54 patients were included, with a mean age of 74.4 years (range 28-109). 30 were male (55.6%), and predominantly Caucasian (79.6%). The main risk factor was prolonged sun exposure (79.6%). Leukoplakic appearance (48.1%), location in bulbar conjunctiva (48.2%) and T3 (46.3%) stage were the most common clinical features. Histologically, the percentage of CIN I, CIN II, CIN III and SCC were 25.9%, 29.6%, 40.7% and 3.7%, respectively. Complete resolution was obtained in 74.1% and tolerance was overall positive. The cost was significantly higher for IFNα (1025€ ± 130.68€) compared to 5-FU (165.57€ ± 45.85 €) (p 0.001). The CEI was - 247.14€. CONCLUSIONS: Both 5-FU and IFN α-2b are effective and present a good security profile as adjuvant therapies after surgery in OSSN. Although presenting slightly more ocular complications, 5-FU can be considered more cost-effective than IFN α-2b.

Nivolumab plus ipilimumab versus the EXTREME regimen in recurrent/metastatic squamous cell carcinoma of the head and neck: a cost-effectiveness analysis.

In the CheckMate 651 study, nivolumab plus ipilimumab versus EXTREME (cisplatin/carboplatin + cetuximab + fluorouracil) regimen was compared for effectiveness. It is not known whether these immunotherapy agents are cost-effective for recurrent or metastatic squamous cell carcinomas of the head and neck (R/M SCCHN). The purpose of this study was to compare the cost-effectiveness of nivolumab plus ipilimumab with EXTREME in the first-line setting from the standpoint of third-party payers in the United States. The projecting of costs and outcomes over 15 years was done using a three-state partitioned survival model discounted by 3% per year. Long-term extrapolation of CheckMate 651 was used to model progression-free survival and overall survival (OS). The incremental net health benefit (INHB), incremental net monetary benefit (INMB), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated. The uncertainty and stability of the model were accounted for via one-way and probabilistic sensitivity analyses. As compared with nivolumab plus ipilimumab, EXTREME was associated with an increase of 0.154 life-years and 0.076 QALYs, as well as a cost increase of $572 per patient. The corresponding ICERs were $7545/QALY along with the values of INMB and INHB were $113,267 and 0.076 QALYs, respectively, at a willingness to pay (WTP) threshold of $150,000/QALY. The probability of nivolumab plus ipilimumab being cost-effective was > 99% in patients with combined positive score (CPS) ≥ 1, CPS 1-19, or CPS ≥ 20. Moreover, hazard ratio for OS and body weight were the most sensitive parameters for the model. According to sensitivity analyses, these results were generally robust. In overall populations with R/M SCCHN, the EXTREME regimen is cost-effective compared with nivolumab plus ipilimumab. Given a WTP threshold of $150,000 per QALY, the probability of the EXTREME regiment being cost-effective compared with nivolumab and ipilimumab, was 64%. Importantly, there was heterogeneity in the cost-effectiveness probabilities, based on primary sites and expression levels of PD-L1. Therefore, tailored treatment based on individual patient and clinical characteristics, remains important, and may impact the cost-effectiveness of the regimens under study.

Cost-effectiveness of immunotherapies for advanced squamous non-small cell lung cancer: a systematic review.

BACKGROUND: There are differences in the pharmacoeconomics of Immune checkpoint blocking (ICB) therapies for the treatment of lung squamous cell carcinoma (LSCC). However, no corresponding review studies have fully discussed the cost-effectiveness of ICBs in treating LSCC. The aim of this paper is to systematically review and evaluate all available pharmacoeconomic studies of ICBs for LSCC. METHOD: The inclusion criteria were based on the population, intervention, comparator, outcomes, and study designs. An electronic search was conducted by June 2023, and the following databases were used: PubMed, EMBASE, Cochrane Library, and Web of Science. Search keywords included 'Carcinoma', Non-Small-Cell Lung', 'Immunotherapy', and 'Economics, Medical'. The primary outcome was the cost-effectiveness analysis of ICB therapy in LSCC patients. Drummond Checklist was used to assess quality problems and possible bias in the study design of included pharmacoeconomic studies. RESULTS: This review searched 15 articles on the economic evaluation of ICB treatment for LSCC. After a qualitative review of 15 studies, we concluded that nivolumab is more cost-effective as a monotherapy than chemotherapy alone. In the combination regimen, pembrolizumab combined with chemotherapy appears to be the most cost-effective option at present, but for Chinese payers with LSCC, locally developed treatments such as sintilimab or toripalimab in combination with chemotherapy are more cost-effective. DISCUSSION: The inclusion of economic evaluation has heterogeneity in research design and outcomes, which can only support qualitative synthesis. Therefore, The results of this paper need to be treated with caution. For the Chinese market, instead of imported drugs, the possible cost-effectiveness of locally developed ICB therapies should be the focus of future research.

Individualized treatment decision model for inoperable elderly esophageal squamous cell carcinoma based on multi-modal data fusion.

BACKGROUND: This research aimed to develop a model for individualized treatment decision-making in inoperable elderly patients with esophageal squamous cell carcinoma (ESCC) using machine learning methods and multi-modal data. METHODS: A total of 189 inoperable elderly ESCC patients aged 65 or older who underwent concurrent chemoradiotherapy (CCRT) or radiotherapy (RT) were included. Multi-task learning models were created using machine learning techniques to analyze multi-modal data, including pre-treatment CT images, clinical information, and blood test results. Nomograms were constructed to predict the objective response rate (ORR) and progression-free survival (PFS) for different treatment strategies. Optimal treatment plans were recommended based on the nomograms. Patients were stratified into high-risk and low-risk groups using the nomograms, and survival analysis was performed using Kaplan-Meier curves. RESULTS: The identified risk factors influencing ORR were histologic grade (HG), T stage and three radiomic features including original shape elongation, first-order skewness and original shape flatness, while risk factors influencing PFS included BMI, HG and three radiomic features including high gray-level run emphasis, first-order minimum and first-order skewness. These risk factors were incorporated into the nomograms as independent predictive factors. PFS was substantially different between the low-risk group (total score ≤ 110) and the high-risk group (total score > 110) according to Kaplan-Meier curves (P < 0.05). CONCLUSIONS: The developed predictive models for ORR and PFS in inoperable elderly ESCC patients provide valuable insights for predicting treatment efficacy and prognosis. The nomograms enable personalized treatment decision-making and can guide optimal treatment plans for inoperable elderly ESCC patients.

Cost-effectiveness of camrelizumab plus chemotherapy in advanced squamous non-small-cell lung cancer.

Objectives: A cost-effectiveness study of camrelizumab plus chemotherapy for advanced squamous non-small-cell lung cancer in China was conducted versus chemotherapy alone. Methods: Survival data were derived from CameL-Sq. Cost-effectiveness is indicated by an incremental cost-effectiveness ratio (ICER) less than the willingness-to-pay threshold. The partitioned survival model stability was assessed by sensitivity analyses. Results: With camrelizumab plus chemotherapy, quality-adjusted life years increased by 0.83, and cost increased by $21,259/patient versus chemotherapy. The ICER was $25,674/quality-adjusted life year. The probability of cost-effectiveness was >90% regardless of PD-L1 expression level. Regardless of the variation in each parameter across a wide range, the ICER never transcended the willingness to pay. Conclusion: Camrelizumab plus chemotherapy is a cost-effective first-line treatment for advanced squamous non-small cell lung cancer in China.

Camrelizumab is a drug, and this drug can be used for advanced squamous non-small-cell lung cancer. Our study showed that patients with non-small-cell lung cancer treated with camrelizumab plus chemotherapy are related to an acceptable price and better clinical outcomes compared with chemotherapy in China. Benefit groups include patients under 65 years of age or over 65, male patients, patients who were current or former smokers and those with or without liver or brain metastases.

Real-world analysis of cost, treatment patterns, and outcomes of patients with metastatic cutaneous squamous cell carcinoma in the US.

OBJECTIVES: To describe real-world characteristics and treatment patterns of patients with metastatic cutaneous squamous cell carcinoma (mCSCC). METHODS: This retrospective observational study used MarketScan Commercial and Medicare Supplemental claims databases (1/1/2013-7/31/2019). Adult patients with mCSCC who initiated non-immunotherapy systemic treatment (i.e. index event) between 1 January 2014 and 31 December 2018 were assessed for treatment patterns, all-cause and CSCC-related healthcare resource utilization, costs, and mortality . RESULTS: Overall, 207 patients were included in the study(mean age 64.8 years, 76.3% male), 59.4% had prior radiotherapy, and 58.9% had prior CSCC-related surgery. During follow-up, 75.8%, 51.7%, and 35.7% of patients received chemotherapy, radiotherapy, and targeted therapy as first-line treatment, respectively. Cisplatin (32.9%) and carboplatin (22.7%) were the most common chemotherapy agents, and cetuximab (32.4%) was the most common targeted therapy during the first-line.Probability of death (95% CI) at month 6, year 1, and year 2 was 24% (16-32%), 50% (40 - 59%), and 67% (56 - 75%), respectively. Average CSCC-related healthcare costs were $5,354 per person per month (PPPM), with outpatient costs being the major cost driver at 96.4% ($5,160 PPPM). CONCLUSION: During 2014-2018, patients with mCSCC were commonly treated with cisplatin and cetuximab; prognosis was generally poor. These results indicate opportunity for new treatments to improve survival outcomes.

Effectiveness and cost-effectiveness analysis of 11 treatment paths, seven first-line and three second-line treatments for Chinese patients with advanced wild-type squamous non-small cell lung cancer: A sequential model.

Background: A total of 11 treatment sequences for advanced wild-type squamous non-small cell lung cancer are recommended by Chinese Society of Clinical Oncology Guidelines, consisting of seven first-line and three second-line treatments. Five of these treatments were newly approved in China between 2021 and 2022. We evaluated the effectiveness and cost-effectiveness of these strategies from the Chinese healthcare system perspective. Methods: Network meta-analysis with non-proportional hazards was used to calculate the relative efficacy between interventions. A sequential model was developed to estimate costs and quality-adjusted life years (QALY) for treatment sequences with first-line platinum- and paclitaxel-based chemotherapy (SC) with or without nedaplatin, tislelizumab, camrelizumab, sintilimab, sugemalimab or pembrolizumab, followed by second-line docetaxel, tislelizumab or nivolumab. SC and docetaxel were used as comparators for first-line and second-line treatments, respectively. QALY and incremental cost-effectiveness ratio (ICER) were used to evaluate effectiveness and cost-effectiveness, respectively. Cost-effective threshold was set as USD 19,091. Subgroup analysis was conducted to determine the best first-line and second-line therapy. Results: Pembrolizumab + SC, followed by docetaxel (PED) was the most effective treatment sequence. QALYs for patients received SC, nedaplatin + SC, tislelizumab + SC, sintilimab + SC, camrelizumab + SC, sugemalimab + SC, pembrolizumab + SC followed by docetaxel were 0.866, 0.906, 1.179, 1.266, 1.179, 1.266, 1.603, 1.721, 1.807; QALYs for SC, nedaplatin + SC followed by tislelizumab were 1.283, 1.301; QALYs for SC, nedaplatin + SC followed by nivolumab were 1.353, 1.389. Camrelizumab + SC, followed by docetaxel (CAD) was the most cost-effective. Compared to SC with or without nedaplatin, tislelizumab, or sintilimab followed by docetaxel, ICERs of CAD were USD 12,276, 13,210, 6,974, 9,421/QALY, respectively. Compared with nedaplatin or SC followed by tislelizumab, the ICERs of CAD were USD 4,183, 2,804/QALY; CAD was dominant compared with nedaplatin or SC followed by nivolumab; The ICER of sugemalimab + SC followed by docetaxel and PED were USD 522,023, 481,639/QALY compared with CAD. Pembrolizumab + SC and camrelizumab + SC were the most effective and cost-effective first-line options, respectively; tislelizumab was the most effective and cost-effective second-line therapy. Tislelizumab used in second-line was more effective than first-line, no significant differences between their cost-effectiveness. Sensitivity and scenario analysis confirmed robustness of the results. Conclusions: PED and CAD are the most effective and cost-effective treatment sequence, respectively; pembrolizumab + SC and camrelizumab + SC are the most effective and cost-effective first-line choice, respectively; tislelizumab is the most effective and cost-effective second-line choice.

Cemiplimab (Libtayo®) en carcinoma cutáneo de células escamosas avanzado / Cemiplimab (Libtayo®) in advanced cutaneous squamous cell carcinoma

INTRODUCCIÓN: El carcinoma escamoso es el segundo tumor de piel más frecuente y el responsable de al menos el 20 % de las muertes asociadas al cáncer cutáneo. Junto a las neoplasias malignas de células basales son conocidos colectivamente como cánceres de piel no melanocíticos o carcinomas de queratinocitos. Varios factores de riesgo están asociados con su desarrollo sin embargo el carcinógeno ambiental más reconocido es la luz solar. Afecta principalmente a personas de edad avanzada debido a la acumulación del daño solar o de la exposición a carcinógenos, así como también en poblaciones específicas como los inmunodeprimidos. En estadios tempranos los objetivos principales del tratamiento del cáncer de piel de células escamosas son la extirpación completa del tumor y la preservación máxima de la función y la estética. Generalmente tienen un buen pronóstico, con una sobrevida mayor del 90% a los 5 años. Sin embargo, hasta un 4-6 % de los pacientes presentarán recidivas locorregionales y metástasis a distancia, con sobrevidas a 10 años del 20% en el caso de la enfermedad locorregional avanzada y menor del 10% en el de la enfermedad metastásica. 1­3 En estos pacientes la radioterapia puede indicarse en tumores no resecables o en aquellas personas que no sean operables. El tratamiento sistémico se reserva para los casos que no pueden tratarse con intención curativa ni mediante cirugía y/o radioterapia debido a una extensa diseminación local y/o regional o ante la existencia de metástasis distantes. Dentro de las opciones se encuentran el uso de inhibidores del punto de control inmunitario (ej. pembrolizumab), el uso de quimioterapia sistémica (ej. carboplatino más paclitaxel) o inhibidores del receptor del factor de crecimiento epidérmico (ej. Cetuximab. En este documento se plantea evaluar la eficacia y seguridad del uso de cemiplimab en pacientes con diagnóstico de carcinoma cutáneo de células escamosas avanzado. TECNOLOGÍA: Cemiplimab es un anticuerpo monoclonal humanizado (tipo IgG4) que se une al receptor de muerte celular programada 1 (PD-1) y bloquea su interacción con sus ligandos PD-L1 y PD-L2. El receptor PD-1 es un regulador negativo de la actividad de las células T, involucrado en el control de las respuestas inmunitarias. El bloqueo selectivo de las interacciones de PD-L1/PD-1 y PD-L1/CD80 potencia las respuestas inmunitarias antitumorales e incrementa la activación de las células T. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de cemiplimab en pacientes con diagnóstico de carcinoma cutáneo de células escamosas avanzado. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. EVIDENCIA CLÍNICA: Rischin y col. publicaron en el año 2021 los resultados de un ensayo clínico abierto y no aleatorizado con el objetivo de evaluar la eficacia y la seguridad cemiplimab en adultos con diagnóstico de carcinoma cutáneo de células escamosas metastásico o localmente avanzado que no son candidatos para cirugía o radioterapia (estudio de fase II denominado R2810-ONC1540; NCT02760498). 6 Fueron excluidos aquellos pacientes enfermedad autoinmune que requirió tratamiento sistémico con agentes inmunosupresores en los últimos 5 años; historia de trasplante de órgano sólido; tratamiento previo con anti-PD-1/PD-L1 entre otras situaciones clínicas. El objetivo primario del estudio fue la tasa de respuesta objetiva confirmada (TRO), evaluada mediante una revisión central independiente. Los pacientes fueron enrolados en tres cohortes: pacientes con enfermedad metastásica (cohortes 1 y 3) o localmente avanzada (cohorte 2). Las cohortes 1 y 2 recibieron cemiplimab a una dosis de 3 mg/kg cada dos semanas, mientras que la cohorte 3 lo recibió 350 mg cada tres semanas. CONCLUSIONES: La evidencia que sustenta la aprobación de comercialización de cemiplimab en adultos con carcinoma cutáneo de células escamosas metastásico o localmente avanzado que no son candidatos a tratamiento curativo se basa en un único ensayo clínico no aleatorizado. Este estudio mostraría que en aquellos pacientes que utilizaron cemiplimab las tasas de respuesta serían cercanas al 46,1% y que el 17,% de los participantes experimentaría eventos adversos severos al mediano plazo. La seguridad y eficacia frente a otras opciones disponibles no puede ser establecida debido a que no se encontraron estudios comparativos. Las recomendaciones relevadas lo mencionan como una opción terapéutica más para el tratamiento en pacientes con carcinoma cutáneo de células escamosas metastásico o localmente avanzado que no han recibido previamente otro inhibidor de puntos de control. Su comercialización en la indicación evaluada se encuentra autorizada por las agencias regulatorias de los Estados Unidos y Europa; sin embargo, en Reino Unido y Canadá su cobertura se haya limitada a un acuerdo de comercialización con un descuento en el precio de venta. Utilizando precios de referencia internacionales el costo de adquisición para un ciclo de tratamiento oscilaría de los 5.500 a 10.000 dólares.

Cost-effectiveness of first-line versus second-line use of domestic anti-PD-1 antibody sintilimab in Chinese patients with advanced or metastatic squamous non-small cell lung cancer.

BACKGROUND: Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/L1) inhibitor is a promising therapeutic option that can be used as either a first-line or second-line treatment for driver-negative advanced or metastatic squamous non-small cell lung cancers (sqNSCLC). However, reuse of PD-1/L1 inhibitor in second-line beyond progression after the first-line is generally not recommended. Therefore, oncologists face challenges in making a proper decision of using PD-1/L1 inhibitor. This analysis aimed to determine whether it is more cost-effective to use sintilimab, a domestic anti-PD-1 drug in China, as a first-line treatment than reserving it until second-line. METHODS: We conducted a cost-effectiveness analysis to compare the use of sintilimab in the first-line setting with reserving its use until the second-line for driver-negative advanced or metastatic sqNSCLC from the perspective of the Chinese healthcare system. A Markov model composed of five main mutually independent health states and three temporary health states was established to simulate patients' clinical trajectory. Transition probabilities, including disease progression, survival, and adverse events-related treatment discontinuation, were estimated using data from the ORIENT-12, ORIENT-3, and ALTER0303 clinical trials. The robustness of the model was assessed using deterministic sensitivity analysis (DSA) and probabilistic sensitivity analyses. RESULTS: Reserving the use of sintilimab until the second-line was associated with a greater effectiveness (1.52 vs. 1.37 quality-adjusted life-years [QALYs]) and a higher healthcare cost ($12,203 vs. $14,045) compared with the first-line sintilimab, resulting in an incremental cost-effectiveness ratio (ICER) of $12,693 per QALY. The results of DSA suggested that variations in all parameters did not result in the ICERs surpassing the willingness-to-pay threshold of $35,663/QALY. CONCLUSIONS: For Chinese patients with driver-negative advanced or metastatic sqNSCLC, reserving the use of sintilimab until the second-line represents a cost-effective treatment strategy compared with the first-line treatment. This finding is useful to inform Chinese healthcare policymakers regarding the optimized treatment strategies of use of domestic PD-1/L1 inhibitors sintilimab.

Cost-effectiveness analysis of sugemalimab in combination with chemotherapy as first-line treatment in Chinese patients with metastatic NSCLC.

INTRODUCTION: Because of its low immunogenicity and associated risk of toxicity, sugemalimab is expected to reshape the first-line treatment landscape for non-small cell lung cancer (NSCLC) in China. However, it remains unclear whether the use of expensive sugemalimab is cost-effective in this population. METHODS: A Markov model was constructed based on the GEMSTONE-302 study to assess the efficacy of sugemalimab in combination with chemotherapy for first-line treatment of metastatic NSCLC. Efficacy and safety data were entered, with costs and utility values derived from the literature, and incremental cost-effectiveness ratios (ICERs) were estimated, and univariate sensitivity analyses and probabilistic sensitivity analyses were performed. We also considered cost-effectiveness in two different treatment regimen scenarios after disease progression. RESULTS: Compared with the placebo plus platinum-based chemotherapy, patients with metastatic NSCLC treated with sugemalimab plus platinum-based chemotherapy saw an increase of 0.56 life-years (LYs) and 0.41 quality-adjusted life-years (QALYs), and patients with squamous NSCLC resulted in an ICER per QALY of $45,280.02. Patients with nonsquamous metastatic NSCLC resulted in an ICER of $45,294.15 per QALY. Univariate sensitivity analysis showed that disease-free survival utility had the greatest impact on the results. Probabilistic sensitivity analysis (PSA) showed that when the willingness-to-pay (WTP) for QALYs was $27,354/QALY, sugemalimab, in combination with platinum-based chemotherapy, was more cost-effective than the placebo. CONCLUSION: From a Chinese health care system perspective, first-line treatment of squamous or nonsquamous metastatic NSCLC with sugemalimab plus platinum-based chemotherapy may have cost-effectiveness compared with placebo plus platinum-based chemotherapy at a WTP threshold of $27,354/QALY.

Eficacia y seguridad del uso de pembrolizumab en pacientes con cáncer de piel de células escamosas en enfermedad metastásica / Efficacy and safety of pembrolizumab use in patients with squamous cell skin cancer in metastatic disease

INTECEDENTES: Mediante Decreto Supremo N° 004-2022-SA, de fecha 30 de marzo de 2022, se aprobó el Reglamento de la Ley N° 31336, Ley Nacional del Cáncer; la cual establece disposiciones técnicas para implementar la Ley, entre ellas: El Instituto Nacional de Salud (INS) en coordinación con la Red Nacional de Evaluación de Tecnologías Sanitarias (RENETSA), elaborará y aprobará los documentos normativos necesarios para realizar las evaluaciones de tecnologías sanitarias (ETS) multicriterio de tal forma que todos sus miembros estandaricen sus procesos de ETS; y el Ministerio de Salud (MINSA) elaborará y aprobará los documentos normativos que establezcan el umbral de alto costo para el tratamiento de enfermedades oncológicas. Sin embargo, a la fecha aún no se han publicado ninguno de estos documentos; por lo que, no se podría determinar qué medicamentos superarían el umbral de alto costo y tendrían que ser remitidos a RENETSA. Por lo tanto, con los elementos disponibles a la fecha, aún no se puede seguir el proceso establecido en el Decreto Supremo N° 004-2022-SA y para evitar retrasar la atención de los asegurados el IETSI continua con el proceso de evaluación de tecnologías sanitarias de acuerdo a lo establecido en la Directiva N° 003-IETSI-ESSALUD-2016, "Normativa para la autorización y uso de productos farmacéuticos no incluidos en el Petitorio Farmacológico de EsSalud", proceso que se encuentra enmarcado en la normativa nacional. ASPECTOS GENERALES: El carcinoma de células escamosas (CCE), se origina en las células escamosas de la capa externa de la piel y en las membranas mucosas. Estas últimas recubren las vías respiratorias y los intestinos. Cuando el cáncer se desarrolla en el epitelio mucoso de la cavidad oral, laringe o/y faringe, se le conoce específicamente como carcinoma de células escamosas de cabeza y cuello (HNSCC, por sus siglas en inglés)(Johnson et al. 2020). Este tipo específico de CCE, está fuera del alcance de la presente evaluación. Por otro lado, cuando este se desarrolla en la piel, se denomina CCE de piel o cutáneo. La presente evaluación, es con respecto al CCE de piel o cutáneo. METODOLOGÍA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad del uso de pembrolizumab en pacientes con CCE de piel en enfermedad metastásica. Esta búsqueda se realizó utilizando los buscadores: National Library of Medicine (PubMed-MEDLINE), Cochrane Library, Web of Science y LILACS. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica, tales como The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH), Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), Institute for Quality and Efficiency in Health Care (IQWiG), Scottish Medicines Consortium (SMC), Comissáo nacional de incorporaoáo de tecnologías no sus (CONITEC), Scottish Intercollegiate Guidelines Network (SIGN), el portal de la Base V. PE TA A 1. Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), el 01. repositorio institucional de la DIGEMID, entre otras. Esta búsqueda se completó revisando tu9 publicaciones de grupos dedicados a la educación, investigación y mejora de la práctica clínica oncológica y dermatológica dentro de América y Europa, como The National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), uropean Society for Medical Oncology (ESMO) y British Association of Dermatologists (BAD). ). Finalmente, se realizó una búsqueda adicional en la página web del registro de ensayos clínicos administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.gov e International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para poder identificar ensayos clínicos en curso o cuyos resultados no hayan sido publicados para, de este modo, disminuir el riesgo de sesgo de publicación. Las estrategias de la búsqueda para identificar la evidencia de ECA se encuentran en las Tabla A, B, C y D del Material Suplementario. RESULTADOS: Luego de la búsqueda realizada hasta el 5 de julio del 2022, se identificaron e incluyeron en el presente documento la guía de NCCN V2.2002 de cáncer de piel de células escamosas (NCCN 2022), la guía de BAD para el manejo de personas con carcinoma cutáneo de células escamosas (Keohane et al. 2021) y tres publicaciones del ensayo pivotal de aprobación de uso de pembrolizumab en pacientes con CCE de piel recurrente o metastásico: KEYNOTE-629 (Grob et al. 2020; Hughes, Munoz-Couselo, et al. 2021; Hughes, Mendoza, et al. 2021). Se excluyeron dos publicaciones, la de Geiger et al., 2019 y Mehta et al., 2021. La primera publicación por Geiger et al., por ser un documento tipo resumen de congreso donde se presentan resultados del ECA KEYNOTE-630 de fase III, el cual incluye pacientes con enfermedad de alto riesgo localmente avanzada, luego de resección quirúrgica y radioterapia; los cuales no pertenecen a la población objetivo del presente dictamen. Por su parte, la publicación de Mehta et al., fue excluida porque esta es una RS con MA cuyo objetivo es evaluar el uso de inmunoterapia en general, por lo cual no solo evaluó estudios en relación a pembrolizumab. Con respecto a la evidencia específica de pembrolizumab considerada en Mehta et al., esta incluye la publicación de Yushack et al., 2019, el cual es un resumen de congreso; la publicación de Maubec et al., 2020, que es un ensayo pequeño (n=57), de fase II no comparativo, donde no se incluyeron pacientes que hubieran recibido quimioterapia curativa o en adyuvancia; y la publicación de Grob et al., 2020 del ensayo KEYNOTE-629 de fase II no comparativo, el cual ya se encuentra incluido en la presente evaluación por ser el ensayo pivotal de aprobación de pembrolizumab en la población de interés. CONCLUSIÓN: Por todo lo expuesto, el IETSI no aprueba el uso de pembrolizumab en pacientes con cáncer de piel de células escamosas con enfermedad metastásica.

Economic evaluation of sintilimab plus chemotherapy vs. pembrolizumab plus chemotherapy for the treatment of first-line advanced or metastatic squamous NSCLC.

Background and objective: Sintilimab has superior efficacy and safety in patients with advanced or metastatic squamous non-small cell lung cancer (NSCLC), but its cost-effectiveness in China is unclear. This study is to evaluate the cost-effectiveness of sintilimab plus chemotherapy vs. pembrolizumab plus chemotherapy for locally advanced or metastatic squamous NSCLC in China. Methods: From the perspective of the Chinese health system, the partitioned survival model with three health states was established in a 3-week cycle and a lifetime time horizon. The two-stage method was used to estimate the overall survival hazard ratios to avoid the bias by crossover design in ORIENT-12 and KEYNOTE-407 studies. The anchored matching adjusted indirect comparison method (MAIC) was used for indirect comparison based on the individual patient data from ORIENT-12 and the publicly published KEYNOTE-407 study due to the lack of head-to-head clinical trials. Only direct medical costs were included, and utilities were derived from the published literature in the base case analysis. Sensitivity analysis was also performed to verify the robustness of the model results. In addition, the scenario analysis where the utilities were derived from the Quality of Life Questionnaire-Core 30 (QLQ-C30) scale in the ORIENT-12 by mapping to the EuroQol-5-dimension 5-level (EQ-5D-5L) was carried out to explore the uncertainty of the results. Results: Compared with pembrolizumab + chemotherapy, sintilimab + chemotherapy incurred a lower lifetime cost ($12,321 vs. 36,371) and yielded fewer quality-adjusted life-years (QALYs) (0.9902 vs. 1.0085), which resulted in an incremental cost-effectiveness ratio (ICER) of $1,314,208/QALY. A sintilimab strategy is a cost-effectiveness option under the WTP of 1-3 times the GDP per capita in China ($11,250/QALY~$33,749/QALY). The utility value of the post-progression, the unit cost of albumin paclitaxel, and the utility value of the progression-free state were the main drivers in the deterministic sensitivity analysis (DSA). According to the probabilistic sensitivity analysis (PSA), sintilimab + chemotherapy was 100% cost-effective when the WTP was 1-3 times China's per capita GDP. The results of the scenario analysis showed that sintilimab + chemotherapy obtained more QALYs (1.2319 vs. 1.1815) and lower costs ($12,321 vs. 36,371), which implied that sintilimab + chemotherapy may dominate the pembrolizumab + chemotherapy. Conclusion: Compared with pembrolizumab + chemotherapy, sintilimab + chemotherapy is more cost-effective for first-line treatment in Chinese patients with locally advanced or metastatic squamous NSCLC.

Assessment of the methylene blue mediated photodynamic therapy on BCL2 and BAX genes expression at mRNA level and apoptosis of head and neck squamous cell carcinoma cell line.

AIM: This study aimed to assess the effect of photodynamic therapy (PDT) on apoptosis of head and neck squamous cell carcinoma (HNSCC) cells by flow cytometry and evaluating BAX and BCL2 genes expression.

Capecitabine in the treatment of anal squamous cell carcinoma.

BACKGROUND: Anal squamous cell carcinoma (ASCC) is a rare tumor; it accounts for about 2% of gastrointestinal tumors. The goal of the treatment is to preserve the anal sphincter and maintain the quality of life; surgical excision is therefore reserved only for very early stages and in vast majority of cases concomitant chemoradiotherapy (CRT) is indicated, i.e. pelvic irradiation and concomitant mitomycin-based chemotherapy. Technological development in the field of radiodia-gnostics, nuclear medicine and radiation therapy has improved the disease staging and enabled more gentle treatment. The standard regimen of chemotherapy has been based on the combination of mitomycin C (MMC) with 5-fluorouracil (5-FU) for many years, with high toxicity. PURPOSE: The administration of 5-FU + capecitabine regimen provided an opportunity to reduce acute haematological toxicity. A prospective randomized phase II trial EXTRA demonstrated the oncological safety and good toxicity profile of oral capecitabine administered instead of 5-FU. The reduction of severe haematological toxicity and oncological non-inferiority of the capecitabine regimen was also demonstrated by other nine analyses presented in this article. CONCLUSION: Most international guidelines published by societies such as the National Comprehensive Cancer Network, the European Society for Medical Oncology or the European Society for Therapeutic Radiology and Oncology have accepted capecitabine as a safe alternative to 5-FU in the treatment of ASCC and CRT regimen with oral capecitabine becoming the standard. The advantages are: proven excellent treatment results (non-inferiority towards standard regimens), significant reduction of various types of toxicity and the convenience of outpatient oral capecitabine.

Cost-effectiveness analysis of pembrolizumab for treatment of US patients with persistent, recurrent, or metastatic cervical cancer.

OBJECTIVE: The effectiveness of pembrolizumab for persistent, recurrent, or metastatic cervical cancer has been demonstrated. We aimed to evaluate its cost-effectiveness from the United States (US) healthcare payers perspective. METHODS: A partitioned survival model over a 30-year lifetime horizon was developed to compare the cost and effectiveness of pembrolizumab versus placebo based on clinical data from the KEYNOTE-826 phase 3 randomized trial. Costs and health state utilities were obtained from literature and publicly available databases. The incremental cost-effectiveness ratio (ICER) was measured. One-way and probabilistic sensitivity analyses were conducted. RESULTS: For the Intention-to-Treat patients, pembrolizumab was associated with an additional 0.74 quality-adjusted life-year (QALY) at an additional cost of $182,271 when compared with placebo. The ICER was $247,663/QALY. For patients with a programmed death-ligand 1 combined positive score ≥ 1 and 10, the ICER was $253,322/QALY and $214,212/QALY, respectively. One-way sensitivity analyses showed that pembrolizumab had the greatest impact on the ICER. Probabilistic sensitivity analyses showed that the probability of pembrolizumab being cost-effective was zero at the current willingness-to-pay threshold of $150,000/QALY. The price of pembrolizumab had to reduce at least to $28.336 (55.8% of the current price) for it to be cost-effective in a 50% of chance. CONCLUSION: The addition of pembrolizumab to chemotherapy is costly and might not be cost-effective for persistent, recurrent, or metastatic cervical cancer at the current price in the US.

Cost-effectiveness analysis of cemiplimab vs pembrolizumab for treatment of advanced cutaneous squamous cell carcinoma.

BACKGROUND: Most cutaneous squamous cell carcinomas (CSCCs) can be treated with surgical excision or radiation; however, approximately 1% of patients develop advanced disease. In 2018, the FDA approved cemiplimab-rwlc as the first programmed cell death-1 (PD-1) monoclonal antibody for the treatment of patients with metastatic CSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation. In June 2020, pembrolizumab, another PD-1 monoclonal antibody, was approved for the treatment of patients with recurrent or metastatic CSCC who are not candidates for curative surgery or radiation. We previously reported on the cost-effectiveness of cemiplimab vs historical standard of care for the treatment of advanced CSCC from a US perspective. OBJECTIVE: To estimate the cost-effectiveness of cemiplimab vs pembrolizumab for patients with advanced CSCC in the United States. METHODS: A "partitioned survival" framework was used to assess the cost-effectiveness of cemiplimab vs pembrolizumab. Clinical inputs were based on the most recent data cut of the phase 2 trials for cemiplimab (EMPOWER-CSCC-1; NCT02760498) and pembrolizumab (KEYNOTE-629). Progression-free survival and overall survival were extrapolated using parametric models until all patients had progressed or died. Health state utilities were derived from data collected in the EMPOWER-CSCC-1 trial. Costs included drug acquisition, drug administration, disease management, terminal care, and adverse events and were based on published 2020 US list prices. To assess model uncertainty, 1-way sensitivity and probabilistic sensitivity analyses (PSA) were conducted, alongside scenario analyses evaluating key modeling assumptions. RESULTS: In the base case, cemiplimab resulted in an incremental gain of 3.44 life-years (discounted) and incremental cost-effectiveness ratio (ICER) of $130,329 per quality-adjusted life-year (QALY) vs pembrolizumab. At a willingness-to-pay threshold of $150,000/QALY, PSA indicated a 71% probability that cemiplimab is cost-effective when compared with pembrolizumab. Scenario analysis resulted in ICERs ranging from $115,909 to $187,374. CONCLUSIONS: Findings suggest that cemiplimab is a cost-effective treatment for patients with advanced CSCC, compared with pembrolizumab. These results should be interpreted cautiously in the absence of head-to-head trials; however, in the absence of such data, these results can be used to inform health care decisions over resource allocation. DISCLOSURES: This study was supported by Regeneron Pharmaceuticals, Inc., and Sanofi. Paul, Cope, Keeping, Mojebi, and Ayers are employees of PRECISIONheor, which received funding to produce this work. Chen, Kuznik, and Xu are employees and stockholders of Regeneron Pharmaceuticals, Inc. Sasane is an employee and stockholder of Sanofi, Inc. Konidaris, Atsou, and Guyot are employees of Sanofi, Inc. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication.

Assessing the Value of Cemiplimab for Adults With Advanced Cutaneous Squamous Cell Carcinoma: A Cost-Effectiveness Analysis.

OBJECTIVES: To evaluate the cost-effectiveness of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC) from a payer perspective in the United States. METHODS: A partitioned survival model was developed to assess the cost-effectiveness of cemiplimab versus historical standard of care (SOC). All inputs were identified based on a systematic literature review, supplemented by expert opinion where necessary. Clinical inputs for cemiplimab were based on individual patient data from a cemiplimab phase 2 single-arm trial (NCT27060498). For SOC, analysis was based on a pooled analysis of single-arm clinical trials and retrospective studies evaluating chemotherapy and epidermal growth factor receptor inhibitors (cetuximab, erlotinib, and gefitinib) identified via a systematic literature review (6 of the 27 included studies). Overall survival and progression-free survival were extrapolated over a lifetime horizon. Costs were included for drug acquisition, drug administration, management of adverse events, subsequent therapy, disease management, and terminal care. Unit costs were based on published 2019 US list prices. RESULTS: In the base case, cemiplimab versus SOC resulted in an incremental cost-effectiveness ratio of $99 447 per quality adjusted-life year (QALY), where incremental costs and QALYs were $372 108 and 3.74, respectively. At a willingness-to-pay threshold of $150 000/QALY, the probabilistic sensitivity analysis suggests a 90% probability that cemiplimab is cost-effective compared to SOC. Scenario analyses resulted in incremental cost-effectiveness ratios ranging from $90 590 to $148 738. CONCLUSIONS: Compared with historical SOC, cemiplimab is a cost-effective use of US payer resources for the treatment of advanced CSCC and is expected to provide value for money.

The role of electrochemotherapy with intratumoral bleomycin for early tongue carcinoma.

BACKGROUND: The role of electrochemotherapy (ECT) using intratumoral bleomycin and electroporation as a first line treatment for oral tongue carcinoma has not been defined. AIMS/OBJECTIVES: To evaluate the method of ECT in oral tongue carcinoma. MATERIAL AND METHODS: Twenty-one successive patients with primary T1-T2 oral cancer predominantly of the oral tongue underwent either ECT (test; n = 9), or standard surgical resection and reconstruction (control; n = 12). Outcome variables were: local recurrence rates, 10-year-survival, adverse events, treatment cost, and quality of life. RESULTS: The 10-year local recurrence rate (44.4%) was higher and the tumour-specific survival rate (55.6%) was lower in the ECT group compared to the control group (17% and 91.6%, respectively). Postoperative haemorrhage, dysphagia, and pain were more frequent in ECT patients, treatment time was shorter, but treatment cost was higher. Quality of life was not improved by ECT. CONCLUSIONS AND SIGNIFICANCE: Our results indicate that ECT seems not as suitable for the treatment of early tongue cancer as it is for neoplastic and metastatic skin lesions and less favourable than standard surgical therapy.