RESUMO
OBJECTIVE: Treating aggressive superficial squamous cell carcinoma (SCC) poses challenges due to invasiveness. Palliative care is recommended for inoperable cases with extensive tumors near vital organs, risking disfigurement or functional impairment. Electrochemotherapy (ECT) is an emerging cutaneous tumor treatment, but its efficacy against superficial SCC remains uncertain. This study conducts a systematic review and single-arm meta-analysis to evaluate ECT's effectiveness against superficial SCC and provide current evidence for clinical practice. METHODS: Embase, PubMed and Cochrane Library were searched for studies up to May 2023. The random effects model analyzed complete response (CR) and partial response (PR), with subgroup assessment based on drug dosage, treatment response evaluation, tumor size, primary/recurrent status, and tumor location. RESULTS: Ten studies involving 162 patients and 208 tumors were included. Pooled CR and PR rates for ECT-treated superficial SCC were 66.5% (95% CI 48.4%-82.5%; I2 = 84%) and 20.3% (95% CI 10.5%-32.3%; I2 = 70%), respectively. Subgroup analysis indicated ECT's superiority in treating primary tumors (PR: 70%, CR: 30%) and tumors ≤ 3 cm (PR: 81.3%, CR: 10.1%) compared to recurrent tumors (PR: 56.7%, CR: 36.5%) and tumors > 3 cm (PR: 45.2%, CR: 34.4%). CONCLUSION: This single-arm meta-analysis confirms ECT's efficacy against superficial SCC, especially in primary tumors and those ≤ 3 cm in diameter. The study highlights the impact of tumor location and response evaluation on ECT's benefits, warranting further investigation through additional research.
Assuntos
Carcinoma de Células Escamosas , Eletroquimioterapia , Neoplasias Cutâneas , Humanos , Eletroquimioterapia/métodos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
OBJECTIVES: To evaluate the efficacy and tolerance after the electrochemotherapy treatment for local therapy of cutaneous and subcutaneous metastases of head-and-neck tumors and malignant melanoma refractory to standard therapies, mainly in neck metastasis of squamous cell carcinoma. And, to evaluate the relation of this response according to the skin reaction (healing with ulcer or dry crust). METHODS: prospective pase II, observational clinical study of 56 patients with metastases of head-and-neck squamous cell carcinoma (n=13), papillary thyroid carcinoma (n=4), adenoid cystic carcinoma of parotid gland (n=1) or malignant melanoma (n=37, 5 in head). Patients were treated by electrochemotherapy (application of electrical pulses into the tumor) after the administration of a single intravenous dose of bleomycin. Kaplan-Meier curves were performed. The statistical significance was evaluated using log-rank test; p-value of less than 0.05 was considered as significant. RESULTS: Overall clinical response was observed in 47 patients (84%). Local side effects were mild in all the patients. Ten patients (76.9%) with neck metastasis of squamous cell carcinoma had some degree of response, but only in one was complete. Patients even with only partial response had a higher overall survival than patients without response (p= 0.02). Most of the patients with squamous cell carcinoma had diminution of pain and anxiety. Response rate and overall survival was higher in MM patients (86.5%) than in squamous cell cancer patients (76.9%) (p= 0.043). The healing process (dry crust/ulcer) was not associated with the overall survival (p= 0.86). CONCLUSIONS: Electrochemotherapy is associated a higher overall survival and diminution of pain and anxiety. Therefore, it is an option as palliative treatment for patients with neck metastasis of squamous cell carcinoma refractory to other therapies or even as a concomitant treatment with newer immunotherapies. The type of healing of the surgical wound could not be associated with a higher rate of response or survival. LEVEL OF EVIDENCE: III.
Assuntos
Carcinoma de Células Escamosas , Eletroquimioterapia , Neoplasias de Cabeça e Pescoço , Melanoma , Neoplasias Cutâneas , Neoplasias da Glândula Tireoide , Humanos , Antibióticos Antineoplásicos/efeitos adversos , Bleomicina/uso terapêutico , Bleomicina/efeitos adversos , Carcinoma de Células Escamosas/patologia , Eletroquimioterapia/efeitos adversos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Melanoma/tratamento farmacológico , Melanoma/induzido quimicamente , Dor/induzido quimicamente , Dor/tratamento farmacológico , Cuidados Paliativos , Estudos Prospectivos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias da Glândula Tireoide/etiologia , Resultado do Tratamento , Úlcera/induzido quimicamente , Úlcera/tratamento farmacológicoRESUMO
Local treatment of canine urothelial carcinoma (UC) of the bladder is a challenge. More than 90% of the cases invade the muscular layer, more than 50% develop on bladder sites with a difficult surgical approach and often requiring radical surgical procedures. This study aims to evaluate the safety and feasibility of electrochemotherapy (ECT) with intravenous bleomycin (BLM) as a local therapy for bladder UC. This prospective study included 21 dogs with spontaneous bladder UC. Regional/distant metastases and neoplastic infiltration of the serosa was considered the main exclusion criteria. We had no deaths during ECT or in the immediate postoperative period, and no suture dehiscence. Most dogs (19/21) developed mild adverse effects, whereas two dogs developed ureteral stenosis. Complete response (CR) was achieved in 62% of the cases (13/21), while partial response (PR) was achieved in 24% (5/21). The median survival and disease-free survival times were 284 and 270 days, respectively. Overall survival was significantly better in the dogs who achieved a CR. In conclusion, ECT was well-tolerated in dogs with UC, demonstrating its safety and feasibility. These data pave the way for new studies aimed at evaluating the effectiveness of ECT in canine bladder UC as a translational model for human disease.
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Carcinoma de Células de Transição , Eletroquimioterapia , Neoplasias Cutâneas , Neoplasias da Bexiga Urinária , Cães , Animais , Humanos , Bleomicina , Antibióticos Antineoplásicos , Estudos Prospectivos , Eletroquimioterapia/métodos , Carcinoma de Células de Transição/tratamento farmacológico , Estudos de Viabilidade , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/veterinária , Neoplasias da Bexiga Urinária/induzido quimicamente , Resultado do Tratamento , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
Electrochemotherapy (ECT) and Irreversible electroporation (IRE) are cancer treatments based on electric field distribution in tissues. Solanum tuberosum (potato tissue) phantom is known to mimic changes in the electrical conductivity that occur in animal tissues during electroporation (EP). Electric field distribution is assessed through enzymatic staining. However, the 24-h wait for this assessment could slow agile response scenarios. We developed and validated the Musa acuminata (cavendish banana) conductivity model, which quickly evaluates EP by tissue staining. We investigated the frequency response of the tissue using impedance spectroscopy analysis, conductivity changes, and enzymatic staining. We optimized three usual EP models: adapted Gompertz, smoothed Heaviside, and the sigmoid or logistic function. We found dielectric parameters in banana tissue similar to those in potato (electrical conductivity of 0.035 S/m and relative permittivity of 4.1×104). The coefficients of determination R2 were 99.94% (Gompertz), 99.85% (Heaviside), and 99.58% (sigmoid). The sigmoid and Heaviside functions described the calibration and validation electric currents with 95% confidence. We observed the electroporated areas in bananas 3h30m after EP. Staining was significant after 450 V/cm. The conductivity model of Musa acuminata suits treatment planning, hardware development, and training scenarios. Banana phantom supports the 3Rs practice and is a reliable alternative for potato in EP studies.
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Eletroquimioterapia , Musa , Animais , Terapia com Eletroporação , Eletroporação , Condutividade ElétricaRESUMO
The convective delivery of chemotherapeutic drugs in cancerous tissues is directly proportional to the blood perfusion rate, which in turns can be transiently reduced by the application of high-voltage and short-duration electric pulses due to vessel vasoconstriction. However, electric pulses can also increase vessel wall and cell membrane permeabilities, boosting the extravasation and cell internalization of drug. These opposite effects, as well as possible adverse impacts on the viability of tissues and endothelial cells, suggest the importance of conducting in silico studies about the influence of physical parameters involved in electric-mediated drug transport. In the present work, the global method of approximate particular solutions for axisymmetric domains, together with two solution schemes (Gauss-Seidel iterative and linearization+successive over-relaxation), is applied for the simulation of drug transport in electroporated cancer tissues, using a continuum tumor cord approach and considering both the electropermeabilization and vasoconstriction phenomena. The developed global method of approximate particular solutions algorithm is validated with numerical and experimental results previously published, obtaining a satisfactory accuracy and convergence. Then, a parametric study about the influence of electric field magnitude and inlet blood velocity on the internalization efficacy, drug distribution uniformity, and cell-kill capacity of the treatment, as expressed by the number of internalized moles into viable cells, homogeneity of exposure to bound intracellular drug, and cell survival fraction, respectively, is analyzed for three pharmacokinetic profiles, namely one-short tri-exponential, mono-exponential, and uniform. According to numerical results, the trade-off between vasoconstriction and electropermeabilization effects and, consequently, the influence of electric field magnitude and inlet blood velocity on the assessment parameters considered here (efficacy, uniformity, and cell-kill capacity) is different for each pharmacokinetic profile deemed.
Assuntos
Eletroquimioterapia , Neoplasias , Humanos , Eletroquimioterapia/métodos , Células Endoteliais , Neoplasias/tratamento farmacológico , Eletroporação/métodos , EletricidadeRESUMO
Squamous cell carcinoma (SCC) is an important malignancy in dogs, due to its incidence and clinical presentation, which can be of locally aggressive single or multiple lesions with a metastatic potential. The objective of this investigation was to evaluate SCC response to treatment, anatomopathological and immunohistochemical characteristics, disease-free interval and overall survival time. 54 dogs with histopathologically diagnosed SCC were included in this study. Their mean age was 9.16 years with a range of 1-14 years. Of the 54 animals in the study, 34 (65.4%) had white skin and white fur coats. There was a significant correlation between fur coat colour and the development of tumours in areas of sun exposure (p = .001). Animals with tumours in areas of the body exposed to the sun had longer overall survival time than animals with tumours in areas not associated with sun exposure (p = .001). Surgery combined with electrochemotherapy (ECT) yielded a survival rate 32% higher than using a surgical approach alone (HR = 0.32, p = .038, IC = 0.11-0.94). ECT, with or without surgery, had an objective response rate of 90.9%. Local lymph node and/or distant site metastasis at diagnosis, or at some point during follow-up, occurred in 34.6% (18/52) of animals. Animals with tumours in sun exposed locations had more aggressive histopathological characteristics but had longer overall survival time. This is probably due to individualised therapeutic treatment with both surgery and ECT.
Assuntos
Carcinoma de Células Escamosas , Doenças do Cão , Eletroquimioterapia , Neoplasias Cutâneas , Cães , Animais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/veterinária , Neoplasias Cutâneas/patologia , Bleomicina/uso terapêutico , Eletroquimioterapia/veterinária , Doenças do Cão/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/veterinária , Carcinoma de Células Escamosas/patologiaRESUMO
Determining cell proliferation rates and tumor apoptosis through immunohistochemistry allows the evaluation of the biological behavior of the tumor, optimizing the patient's clinical course. This study aimed to analyze the immunohistochemical expression of Ki-67, COX-2 and caspase-3 and correlate them with the type of response to ECT in feline cutaneous squamous cell carcinoma (SCC), thus determining the predictive potential of these variables. For this, 13 samples of feline cutaneous SCC were evaluated before ECT, and statistical analyses of the correlation intensity between the variables were performed using the Spearman correlation coefficient, with a significance level of 95%. The results indicate a significant negative correlation between histopathological grade and response to ECT (ρ=-0.6; p=0.03); there was no significant correlation between Ki-67, COX-2 and caspase-3 immunoexpression with the response to ECT (ρ=-0.18; p=0.54/ρ=-0.23; p=0.44/ρ=-0.12; p=0.69, respectively). Therefore, the study shows that the histopathological grade, tumor size and staging, degree of cellular pleomorphism and degree of inflammatory infiltrate can be considered negative prognostic factors for cutaneous SCC and negative predictors for response to ECT. However, the markers Ki-67, COX-2 and caspase-3 are not considered predictive factors for the type of response to ECT. In addition, no relationship between these immunoexpressions and greater tumor aggressiveness was observed. The SCCs evaluated in this study showed significant COX-2 labeling, indicating a potential therapeutic target. ECT has been shown to be safe and effective for local control of feline cutaneous SCC but with reduced effectiveness in larger and invasive lesions.
A determinação das taxas de proliferação celular e apoptose tumoral por meio da imuno-histoquímica, permite avaliar o comportamento biológico tumoral, com otimização da evolução clínica do paciente. Este trabalho teve como objetivo analisar as expressões imuno-histoquímicas de Ki-67, COX-2 e caspase-3 e correlacioná-las com o tipo de resposta à EQT em carcinoma de células escamosas (CEC) cutâneo de felinos; assim, determinar o potencial preditivo destas variáveis. Para tanto, foram avaliadas 13 amostras de CEC cutâneo de felinos antes da EQT e as análises estatísticas quanto à intensidade de correlação entre as variáveis foram realizadas utilizando o coeficiente de correlação de Spearman, com nível de significância de 95%. Os resultados indicam que houve correlação negativa significativa entre o grau histopatológico e a resposta à EQT (ρ=-0,6; p=0,03); não houve correlação significativa entre as imunoexpressões de Ki-67, COX-2 e caspase-3 com a resposta à EQT (ρ=-0,18; p=0,54/ρ=-0,23; p=0,44/ρ=-0,12; p=0,69, respectivamente). Portanto, este estudo evidenciou que as variáveis grau histopatológico, tamanho e estadiamento tumorais, grau de pleomorfismo celular e grau do infiltrado inflamatório foram consideradas fatores prognósticos negativos para o CEC cutâneo e preditivos negativos para a resposta à EQT. Entretanto, os marcadores Ki-67, COX-2 e caspase-3 não foram considerados fatores preditivos para o tipo de resposta à EQT, assim como não foi observada relação entre essas imunoexpressões com maior agressividade tumoral. Os CECs avaliados neste estudo apresentaram importante marcação para COX-2, indicando um potencial alvo terapêutico. A EQT mostrou-se segura e efetiva para o controle local dos CECs cutâneos dos felinos, porém com efetividade reduzida em lesões maiores e invasivas.
Assuntos
Animais , Gatos , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/veterinária , Doenças do Gato , Biomarcadores Tumorais , Antígeno Ki-67 , Caspase 3 , Eletroquimioterapia/veterináriaRESUMO
Electrochemotherapy is a selective electrical-based cancer treatment. A thriving treatment depends on the local electric field generated by pairs of electrodes. Electrode damage as deflection can directly affect this treatment pillar, the distribution of the electric field. Mechanical deformations such as tip misshaping and needle deflection are reported with needle electrode reusing in veterinary electrochemotherapy. We performed in vitro and in silico experiments to evaluate potential problems with ESOPE type II electrode deflection and potential treatment pitfalls. We also investigated the extent to which the electric currents of the electroporation model can describe deflection failure by comparing in vitro with the in silico model of potato tuber (Solanum tuberosum). The in silico model was also performed with the tumor electroporation model, which is more conductive than the vegetal model. We do not recommend using deflected electrodes. We have found that a deflection of ± 2 mm is unsafe for treatment. Inward deflection can cause dangerous electrical current levels when treating a tumor and cannot be described with the in silico vegetal model. Outward deflection can cause blind spots in the electric field.
Assuntos
Simulação por Computador , Condutividade Elétrica , Eletroquimioterapia , Modelos Teóricos , Neoplasias/tratamento farmacológico , Humanos , AgulhasRESUMO
The use of electrochemotherapy (ECT) is a well-established technique to increase the cellular uptake of cytotoxic agents within certain cancer treatment strategies. The study of the mechanisms that take part in this complex process is of high interest to gain a deeper knowledge of it, enabling the improvement of these strategies. In this work, we present a coupled multi-physics electroporation model based on a related previous one, to describe the effect of a set of electric pulses on cisplatin transport across the plasma membrane. The model applies a system of partial differential equations that includes Poisson's equation for the electric field, Nernst-Planck's equation for species transport, Maxwell's tensor and mechanical equilibrium equation for membrane deformation and Smoluchowski's equation for pore creation dynamics. Our numerical results were compared with previous numerical and experimental published data with good qualitative and quantitative agreement. These results indicate that pore aperture is favored at the cell poles by the electric field and mechanical stress forces, giving support to the dominant hypothesis of hydrophilic pore creation as the main mechanism of drug entry during an ECT treatment.
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Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Eletroquimioterapia , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Eletroquimioterapia/métodos , Análise de Elementos Finitos , Humanos , Modelos BiológicosRESUMO
Electroporation (EP), the increase of cell membrane permeability due to the application of electric pulses, is a universal phenomenon with a broad range of applications. In medicine, some of the foremost EP-based tumor treatments are electrochemotherapy (ECT), irreversible electroporation, and gene electrotransfer (GET). The electroporation phenomenon is explained as the formation of cell membrane pores when a transmembrane cell voltage reaches a threshold value. Predicting the outcome of an EP-based tumor treatment consists of finding the electric field distribution with an electric threshold value covering the tumor (electroporated tissue). Threshold and electroporated tissue are also a function of the number of pulses, constituting a complex phenomenon requiring mathematical modeling. We present OpenEP, an open-source specific purpose simulator for EP-based tumor treatments, modeling among other variables, threshold, and electroporated tissue variations in time. Distributed under a free/libre user license, OpenEP allows the customization of tissue type; electrode geometry and material; pulse type, intensity, length, and frequency. OpenEP facilitates the prediction of an optimal EP-based protocol, such as ECT or GET, defined as the critical pulse dosage yielding maximum electroporated tissue with minimal damage. OpenEP displays a highly efficient shared memory implementation by taking advantage of parallel resources; this permits a rapid prediction of optimal EP-based treatment efficiency by pulse number tuning.