Efeito da emulsão clássica de 5-fluorouracil versus 5-fluorouracil manipulado em emulsão com homogeneização de alta velocidade no fotoenvelhecimento avançado e no campo de cancerização dos antebraços
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Data
2024-05-15
Autores
Mestnik, Natalia Cammarosano [UNIFESP]
Orientadores
Bagatin, Ediléia [UNIFESP]
Tipo
Tese de doutorado
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Fundamentos: O fotoenvelhecimento refere-se à associação de alterações biológicas secundárias à exposição solar sobre o envelhecimento intrínseco. A degeneração causada pela radiação ultravioleta (UV) sobre diversas estruturas celulares e moleculares determina diversas alterações cutâneas, entre elas, o câncer de pele. As queratoses actínicas (QAs) múltiplas, uma das características do fotoenvelhecimento avançado, são consideradas lesões pré neoplásicas e constituem o chamado campo de cancerização (CC). Fotoenvelhecimento avançado e CC são fenômenos cutâneos que se desenvolvem paralelamente. O uso tópico de 5-Fluorouracil (5-FU) é aprovado para o tratamento de QAs. No entanto, suas limitações de uso estão associadas aos efeitos colaterais como eritema, descamação, crostas e prurido. Atualmente, o desenvolvimento de medicações tópicas empregando novas tecnologias, como a homogeneização de alta velocidade, visa melhor ou igual eficácia das formulações, com menos eventos adversos. Objetivos: 1) Avaliar a eficácia, perfil de segurança e tolerabilidade através dos efeitos clínicos e histológicos epidérmicos e dérmicos do 5-FU a 5% em emulsão tópica manipulada com homogeneização de alta velocidade (fórmula inovadora), comparada à emulsão tradicional no tratamento do CC e no fotoenvelhecimento avançado dos antebraços de pacientes imunocompetentes. 2) Analisar marcadores envolvidos no CC por meio da análise de imuno-histoquímica e expressão gênica. Métodos: Estudo clínico de fase II de intervenção terapêutica, randomizado, prospectivo, comparativo e duplo-cego. Após aprovação pelo Comitê de Ética em Pesquisa – Unifesp, assinatura do Termo de Consentimento Livre e Esclarecido (TCLE) e do Termo de Autorização para uso de imagens, foram incluídos 41 participantes com fotoenvelhecimento grave ou avançado dos antebraços (classificação de Guimarães, 2015) com QAs múltiplas. O esquema terapêutico compreendeu o uso do 5-FU 5% em emulsão tradicional em um antebraço (grupo Clássico) e em emulsão preparada com homogeneização de alta velocidade no antebraço contralateral (grupo Turrax), definido por randomização, duas vezes ao dia, durante quatro semanas. A avaliação da eficácia incluiu os seguintes parâmetros: 1) Clínicos: avaliação do investigador, através da Escala de Fotoenvelhecimento dos Antebraços (EFA) e contagem de QAs; e de dois observadores independentes por comparação de fotografias padronizadas; 2) Medidas instrumentais não invasivas: corneometria, cutometria e ultrassonografia (USG) de alta frequência. Todas as medidas foram realizadas antes (T0) e após 12 semanas do início do tratamento (T12); 3) Biópsias de pele em T0 e T12, uma em cada antebraço para exames histológico, imuno-histoquímico e análise da expressão gênica e outra biópsia em T0 na região ventral do braço esquerdo em área não fotoexposta para comparação das vias associadas ao envelhecimento extrínseco e intrínseco (controle). A avaliação de segurança baseou-se na observação e relatos de efeitos colaterais. Resultados: Dos 41 participantes incluídos 40 completaram o estudo. Os achados clínicos confirmaram os benefícios do 5-FU 5% tópico, independentemente da formulação utilizada: 1. EFA (média grupo Turrax: T0=100/T12=88, p<0,01; média grupo Clássico: T0=101/T12=87, p<0,01; sem diferença entre os tratamentos); 2. Contagem de QAs (média grupo Turrax: T0=8/T12=0, p<0,001; média grupo Clássico: T0=9/T12=0, p<0,001; sem diferença entre os tratamentos); assim como as medidas não invasivas: corneometria (média grupo Turrax: T0=27,7/T12=33,1, p<0,01; média grupo Clássico T0=29,5/T12=32,6, p=0,04; sem diferença entre os tratamentos); cutometria (número amostral de 19, mediana R7 grupo Turrax T0=0,29/T12=0,51, p<0,01; mediana R7 grupo Clássico T0=0,27/T12=0,47, p<0,01, sem diferença entre os tratamentos); USG: SLEB (subepidermal low echogenic band) (n amostral de 19, Média Grupo Turrax T0=0,36/T12=0,36, p = 0,97; Média Grupo Clássico T0=0,39/T12=0,43, p = 0,21; com diferença entre eles p =0,04). Os achados histológicos (número amostral de 21) demonstraram melhora da classificação da neoplasia intraepidérmica de queratinócitos (KIN) e a tendência da redução da expressão imuno-histoquímica de p53 e Ki-67 epidérmicas em T12 em ambos os grupos. Os efeitos colaterais observados pelo investigador (eritema, descamação, prurido, ressecamento e crostas) ocorreram em todos os casos, em ambos os antebraços, porém, foram de intensidade leve a moderada e não apresentaram diferença estatística entre os tratamentos utilizados. Conclusão: Os tratamentos tópicos com 5-FU a 5% em creme ou preparado com homogeneização de alta velocidade foram eficazes no tratamento do CC e na melhora dos sinais de fotoenvelhecimento dos antebraços.
Background: Photoaging is the association of biological alterations secondary to sun exposure over intrinsic aging. The degeneration caused by ultraviolet (UV) radiation on various cellular and molecular structures determines skin alterations, including skin cancer. Multiple actinic keratoses (AKs), one of the characteristics of advanced photoaging, are considered pre-neoplastic lesions and constitute the so-called cutaneous field cancerization (CFC). Advanced photoaging and CFC are cutaneous phenomena that develop in parallel. The topical use of 5-Fluorouracil (5-FU) is approved for treating AKs. However, its limitations include side effects such as erythema, desquamation, crusting, and pruritus. Currently, the development of topical medications using new technologies, such as high-speed homogenization, aims to improve or equal the efficacy of formulations with fewer adverse events. Objectives: 1) To evaluate the efficacy, safety profile, and tolerability through the clinical and histological epidermal and dermal effects of 5% 5-FU in topical emulsion compounded with high-speed homogenization (innovative formula), compared to traditional emulsion in the treatment of CFC and advanced photoaging of the forearms of immunocompetent patients. 2) To analyze markers involved in CFC through immunohistochemistry and gene expression analysis. Methods: Phase II randomized, prospective, comparative, double-blind therapeutic intervention study. After approval by the Unifesp Research Ethics Committee, signing of the Informed Consent Form (ICF) and the Authorization Form for the use of images, 41 participants with severe or advanced photoaging of the forearms (classification by Guimarães, 2015) with multiple AKs were included. The therapeutic regimen included the use of 5% 5-FU in a traditional emulsion on one forearm (classic group) and an emulsion prepared with high-speed homogenization on the contralateral forearm (Turrax group), defined by randomization twice a day for four weeks. The efficacy evaluation included the following parameters: 1) clinical: evaluation by the investigator, using the Forearm Photoaging Scale (FPS) and AK count, and by two independent observers by comparing standardized photographs; 2) non-invasive instrumental measurements: corneometry, cutometry, and high-frequency ultrasound (US). All measurements were taken before (T0) and 12 weeks after the start of treatment (T12); 3) skin biopsies at T0 and T12, one on each forearm for histological, immunohistochemical, and gene expression analysis and another biopsy at T0 on the ventral region of the left arm in a non-photoexposed area to compare the pathways associated with extrinsic and intrinsic aging (control). The safety assessment was based on observation and reports of side effects. Results: Of the 41 participants included, 40 completed the study. The clinical findings confirmed the benefits of topical 5% 5-FU, regardless of the formulation used: 1. FPS (mean Turrax group: T0=100/T12=88, p<0.01; mean classic group: T0=101/T12=87, p<0.01; no difference between treatments); 2. AK count (mean Turrax group: T0=8/T12=0, p<0.001; mean classic group: T0=9/T12=0, p<0.001; no difference between treatments), as well as non-invasive measurements: corneometry (mean Turrax group: T0=27.7/T12=33.1, p<0.01; classic group mean T0=29.5/T12=32.6, p=0.04; no difference between treatments) and cutometry (sample number 19, median R7 Turrax group T0=0.29/T12=0.51, p<0.01; median R7 classic group T0=0.27/T12=0.47, p<0.01, no difference between treatments); US: SLEB (subepidermal low echogenic band) (sample number 19: mean Turrax group T0=0.36/T12=0.36, p = 0.97; mean Classic group T0=0.39/T12=0.43, p = 0.21; with difference between treatments p =0,04). The histological findings (sample number 21) showed an improvement in the classification of keratinocytic intraepidermal neoplasia (KIN) and a trend toward a reduction in the immunohistochemical expression of epidermal p53 and Ki-67 at T12 in both groups. The side effects observed by the researcher (erythema, scaling, itching, dryness, and crusting) occurred in all cases on both forearms but were mild to moderate in intensity and showed no statistical difference between the treatments used. Conclusion: Topical treatments with 5% 5-FU in cream or prepared with high-speed homogenization were effective in treating CFC and improving the signs of photoaging on the forearms.
Background: Photoaging is the association of biological alterations secondary to sun exposure over intrinsic aging. The degeneration caused by ultraviolet (UV) radiation on various cellular and molecular structures determines skin alterations, including skin cancer. Multiple actinic keratoses (AKs), one of the characteristics of advanced photoaging, are considered pre-neoplastic lesions and constitute the so-called cutaneous field cancerization (CFC). Advanced photoaging and CFC are cutaneous phenomena that develop in parallel. The topical use of 5-Fluorouracil (5-FU) is approved for treating AKs. However, its limitations include side effects such as erythema, desquamation, crusting, and pruritus. Currently, the development of topical medications using new technologies, such as high-speed homogenization, aims to improve or equal the efficacy of formulations with fewer adverse events. Objectives: 1) To evaluate the efficacy, safety profile, and tolerability through the clinical and histological epidermal and dermal effects of 5% 5-FU in topical emulsion compounded with high-speed homogenization (innovative formula), compared to traditional emulsion in the treatment of CFC and advanced photoaging of the forearms of immunocompetent patients. 2) To analyze markers involved in CFC through immunohistochemistry and gene expression analysis. Methods: Phase II randomized, prospective, comparative, double-blind therapeutic intervention study. After approval by the Unifesp Research Ethics Committee, signing of the Informed Consent Form (ICF) and the Authorization Form for the use of images, 41 participants with severe or advanced photoaging of the forearms (classification by Guimarães, 2015) with multiple AKs were included. The therapeutic regimen included the use of 5% 5-FU in a traditional emulsion on one forearm (classic group) and an emulsion prepared with high-speed homogenization on the contralateral forearm (Turrax group), defined by randomization twice a day for four weeks. The efficacy evaluation included the following parameters: 1) clinical: evaluation by the investigator, using the Forearm Photoaging Scale (FPS) and AK count, and by two independent observers by comparing standardized photographs; 2) non-invasive instrumental measurements: corneometry, cutometry, and high-frequency ultrasound (US). All measurements were taken before (T0) and 12 weeks after the start of treatment (T12); 3) skin biopsies at T0 and T12, one on each forearm for histological, immunohistochemical, and gene expression analysis and another biopsy at T0 on the ventral region of the left arm in a non-photoexposed area to compare the pathways associated with extrinsic and intrinsic aging (control). The safety assessment was based on observation and reports of side effects. Results: Of the 41 participants included, 40 completed the study. The clinical findings confirmed the benefits of topical 5% 5-FU, regardless of the formulation used: 1. FPS (mean Turrax group: T0=100/T12=88, p<0.01; mean classic group: T0=101/T12=87, p<0.01; no difference between treatments); 2. AK count (mean Turrax group: T0=8/T12=0, p<0.001; mean classic group: T0=9/T12=0, p<0.001; no difference between treatments), as well as non-invasive measurements: corneometry (mean Turrax group: T0=27.7/T12=33.1, p<0.01; classic group mean T0=29.5/T12=32.6, p=0.04; no difference between treatments) and cutometry (sample number 19, median R7 Turrax group T0=0.29/T12=0.51, p<0.01; median R7 classic group T0=0.27/T12=0.47, p<0.01, no difference between treatments); US: SLEB (subepidermal low echogenic band) (sample number 19: mean Turrax group T0=0.36/T12=0.36, p = 0.97; mean Classic group T0=0.39/T12=0.43, p = 0.21; with difference between treatments p =0,04). The histological findings (sample number 21) showed an improvement in the classification of keratinocytic intraepidermal neoplasia (KIN) and a trend toward a reduction in the immunohistochemical expression of epidermal p53 and Ki-67 at T12 in both groups. The side effects observed by the researcher (erythema, scaling, itching, dryness, and crusting) occurred in all cases on both forearms but were mild to moderate in intensity and showed no statistical difference between the treatments used. Conclusion: Topical treatments with 5% 5-FU in cream or prepared with high-speed homogenization were effective in treating CFC and improving the signs of photoaging on the forearms.
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MESTNIK, Natalia Cammarosano. Efeito da emulsão clássica de 5-fluorouracil versus 5-fluorouracil manipulado em emulsão com homogeneização de alta velocidade no fotoenvelhecimento avançado e no campo de cancerização dos antebraços. 2024. 204 f. Tese (Doutorado em Medicina Translacional) - Escola Paulista de Medidicna, Universidade Federal de São Paulo (UNIFESP). São Paulo, 2024.