5-fluorouracil 5 por cento intermitente versus nicotinamida no tratamento do campo de cancerização cutâneo: ensaio clínico randomizado
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2017-08-24
Autores
Ferreira, Eliane Roio
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Universidade Estadual Paulista (Unesp)
Resumo
O tratamento do campo de cancerização tem o intuito de evitar a progressão das lesões pré-malignas ou desenvolvimento de lesões subclínicas, como forma de prevenção da carcinogênese. Existem diversas propostas de tratamento, porém, há poucos estudos com nicotinamida oral, nenhum comparando a eficácia entre 5-fluorouracil (5FU) tópico com fotoproteção, ou na sua associação com a nicotinamida oral. Objetivos: Avaliação da eficácia da nicotinamida oral, versus 5FU tópico intermitente, e fotoproteção, no tratamento do campo de cancerização cutâneo e queratoses actínicas (QA). Casuística e métodos: Desenho: ensaio clínico randomizado (em blocos), controlado (intrasujeito), duplo cego, fatorial. Participantes: pacientes imunocompetentes, que continham entre três e dez QA cada antebraço, selecionados durante os atendimentos do ambulatório oncológico do serviço de dermatologia da Faculdade de Medicina de Botucatu – UNESP no período de março a setembro de 2016. Houve randomização em blocos e alocação em grupos dos pacientes e antebraços. Intervenção: um grupo recebeu nicotinamida 500mg, via oral, cada 12h, e o outro, placebo. Um dos antebraços recebeu 5FU 5% creme, noturno, 3x por semana, e ambos, filtro solar (FPS 30) diurno. A duração dos tratamentos foi de 120 dias. Os pacientes foram avaliados nos momentos: T0 e T120 para avaliação clínica (contagem de QA, escore de gravidade de QA e escore de fotoenvelhecimento) e biópsia de pele para avaliação do grau de neoplasia intraepitelial dos queratinótitos (KIN), p53 e ki67. Foram avaliados ainda os efeitos adversos no T14. Desfechos: foram analisados por intenção de tratamento (ITT), e os dropouts imputados com os valores da última avaliação disponíveis (LOCF). Os grupos foram comparados por modelo linear generalizado de efeitos mistos. Resultados: Foram incluídos 36 participantes (72 antebraços). A média de idade foi 71,6 (8,6) anos, fototipos I e II prevaleceram (94%) e 61% eram do sexo feminino. Houve redução na contagem de QA para nicotinamida com 5FU (-71%) e com filtro solar (-50%), assim como para placebo e 5FU (-62%) e filtro solar (-60%), 5FU apresentou superioridade ao FPS (p<0,05). O clearance parcial de QA (>50%), apresentou redução para todos os subgrupos (-83%; -50%; -72%; -61%), com superioridade para 5FU (p<0,05). O clearance total de QA não apresentou diferença entre os tratamentos (p=0,72,). Houve redução do escore de gravidade de QA (-74%; -62%; -81%; -64%) e de fotoenvelhecimento (-10%; -6%; -22%; -8%), sem diferença entre os grupos (p>0,2). Os principais efeitos adversos observados foram eritema (50%) e dor local (5%) com uso de 5-FU, epigastralgia e náusea com nicotinamida (5%). Houve redução no escore KIN em todos os grupos (p<0,05), sem diferença entre os subgrupos. Houve redução da atrofia epitelial em todos os tratamentos (p<0,05), com superioridade para 5FU (p<0,05). Houve redução do escore Ki67 em ambos os tratamentos (p<0,05), com maior redução no grupo que recebeu nicotinamida (p<0,05). Para p53 não houve diferença entre os tratamentos (p=0,81). Ocorreram 3 dropouts. Conclusão: 5-FU tópico reduz a atividade do campo de cancerização de forma mais eficaz que o filtro solar quanto à contagem e ao clearance de QA. Nicotinamida oral não promoveu melhora clínica, mas histológica (Ki67), adicional à fotoproteção ou ao uso de 5FU.
Background: The treatment of the skin field cancerization is aimed at preventing the progression of premalignant lesions or the development of subclinical lesions as a way of preventing carcinogenesis. There are several treatment proposals, however, there are few studies with oral nicotinamide, none comparing the efficacy of topical 5-fluorouracil (5FU) with photoprotection, or its association with oral nicotinamide. Objectives: To evaluate the efficacy of oral nicotinamide versus intermittent topical 5FU and photoprotection in the treatment of cutaneous cancer and actinic keratoses (AK). Casuistry and methods: Design: randomized (blocks), controlled (intrasubject), double blind, factorial clinical trial. Participants: immunocompetent patients, who had between 3 and 10 AK each forearm, selected during the visits of the oncology outpatient clinic of the dermatology department of Botucatu Medical School - UNESP from March to September, 2016. There was randomization in blocks and allocation in Groups of patients and forearms. Intervention: one group received nicotinamide 500mg, orally every 12h, and the other, placebo. One of the forearms received 5FU 5% cream, overnight, 3x per week, and both, daytime (SPF 30) sunscreen. The duration of the treatments was 120 days. The patients were evaluated at the moments: T0 and T120 for clinical evaluation (AK score, AK severity score and photoaging score) and skin biopsy for evaluation of the levels of keratinocyte intraepithelial neoplasia (KIN), p53 and ki67. Adverse effects were also evaluated in the T14. Outcomes: were analyzed by intention to treat (ITT), and the imputed dropouts with the values of the last observation carried forward (LOCF). The groups were compared by generalized linear model of mixed effects. Results: 36 participants (72 forearms) were included. The mean age was 71.6 (8.6) years, phototypes I and II prevailed (94%) and 61% were female. There was a reduction in the counts of AK for nicotinamide with 5FU (-71%) and with sunscreen (-50%), as well as for placebo and 5FU (-62%) and sunscreen (-60%), 5FU presented SPF superiority (P <0.05). The partial clearance of AK (> 50%) presented a reduction for all subgroups (-83%, -50%, -72%, -61%), with a superiority of 5FU (p <0.05). Total clearance of AK did not show any difference between the treatments (p = 0.72,). There was a reduction in the severity score of AK (-74%, -62%, -81%, -64%) and of photoaging (-10%, -6%, -22%, -8%), with no difference between Groups (p> 0.2). The main adverse effects observed were erythema (50%) and local pain (5%) with use of 5-FU, epigastralgia and nausea with nicotinamide (5%). There was a reduction in the KIN score in all groups (p <0.05), with no difference between the subgroups. There was reduction of epithelial atrophy in all treatments (p <0.05), with superiority to 5FU (p <0.05). There was a reduction in the Ki67 score in both treatments (p <0.05), with a larger reduction in the nicotinamide group (p <0.05). For p53 there was no difference between treatments (p = 0.81). There were 3 dropouts: one per death, one refusal because the lesions improved, and one drop due to adverse local effects. Conclusion: Topical 5-FU reduces the activity of the cancerization field more effectively than the sunscreen in the counting and clearance of AK. Oral nicotinamide did not promote clinical improvement, but histological improvement (Ki67), additional to photoprotection or the use of 5FU.
Background: The treatment of the skin field cancerization is aimed at preventing the progression of premalignant lesions or the development of subclinical lesions as a way of preventing carcinogenesis. There are several treatment proposals, however, there are few studies with oral nicotinamide, none comparing the efficacy of topical 5-fluorouracil (5FU) with photoprotection, or its association with oral nicotinamide. Objectives: To evaluate the efficacy of oral nicotinamide versus intermittent topical 5FU and photoprotection in the treatment of cutaneous cancer and actinic keratoses (AK). Casuistry and methods: Design: randomized (blocks), controlled (intrasubject), double blind, factorial clinical trial. Participants: immunocompetent patients, who had between 3 and 10 AK each forearm, selected during the visits of the oncology outpatient clinic of the dermatology department of Botucatu Medical School - UNESP from March to September, 2016. There was randomization in blocks and allocation in Groups of patients and forearms. Intervention: one group received nicotinamide 500mg, orally every 12h, and the other, placebo. One of the forearms received 5FU 5% cream, overnight, 3x per week, and both, daytime (SPF 30) sunscreen. The duration of the treatments was 120 days. The patients were evaluated at the moments: T0 and T120 for clinical evaluation (AK score, AK severity score and photoaging score) and skin biopsy for evaluation of the levels of keratinocyte intraepithelial neoplasia (KIN), p53 and ki67. Adverse effects were also evaluated in the T14. Outcomes: were analyzed by intention to treat (ITT), and the imputed dropouts with the values of the last observation carried forward (LOCF). The groups were compared by generalized linear model of mixed effects. Results: 36 participants (72 forearms) were included. The mean age was 71.6 (8.6) years, phototypes I and II prevailed (94%) and 61% were female. There was a reduction in the counts of AK for nicotinamide with 5FU (-71%) and with sunscreen (-50%), as well as for placebo and 5FU (-62%) and sunscreen (-60%), 5FU presented SPF superiority (P <0.05). The partial clearance of AK (> 50%) presented a reduction for all subgroups (-83%, -50%, -72%, -61%), with a superiority of 5FU (p <0.05). Total clearance of AK did not show any difference between the treatments (p = 0.72,). There was a reduction in the severity score of AK (-74%, -62%, -81%, -64%) and of photoaging (-10%, -6%, -22%, -8%), with no difference between Groups (p> 0.2). The main adverse effects observed were erythema (50%) and local pain (5%) with use of 5-FU, epigastralgia and nausea with nicotinamide (5%). There was a reduction in the KIN score in all groups (p <0.05), with no difference between the subgroups. There was reduction of epithelial atrophy in all treatments (p <0.05), with superiority to 5FU (p <0.05). There was a reduction in the Ki67 score in both treatments (p <0.05), with a larger reduction in the nicotinamide group (p <0.05). For p53 there was no difference between treatments (p = 0.81). There were 3 dropouts: one per death, one refusal because the lesions improved, and one drop due to adverse local effects. Conclusion: Topical 5-FU reduces the activity of the cancerization field more effectively than the sunscreen in the counting and clearance of AK. Oral nicotinamide did not promote clinical improvement, but histological improvement (Ki67), additional to photoprotection or the use of 5FU.
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Ceratose actínica, Carcinoma espinocelular, Dermatologia, Oncologia, Quimioprevenção, Fluorouracil, Niacinamida, Actinic keratosis, Chemoprevention, Nicotinamide, Dermatology, Field cancerization, Oncology, Photochemoterapy, Squamous cell carcinoma, 5-Fuorouracil