Primer consenso español sobre el uso de la radioterapia intraoperatoria en el cáncer de mama. Conclusiones del panel de expertos / First Spanish consensus on the use of intraoperative radiotherapy in breast cancer. Conclusions of the expert panel

Introducción: la publicación de ensayos aleatorizados con resultados a largo plazo ha demostrado que la radioterapia intraoperatoria (RIO) en cáncer de mama en estadio precoz puede ser una alternativa terapéutica en casos bien seleccionados. En el presente trabajo se presentan los resultados del Primer Consenso de Radioterapia Intraoperatoria en Cáncer de Mama realizado de manera multidisciplinar en España. Material y método: se hizo una revisión sistemática de la literatura y se invitó a todos los oncólogos radioterápicos y cirujanos expertos en RIO en cáncer de mama de España a participar en el consenso. Se aplico la siguiente metodología en 2 fases: a) la creación de un grupo de trabajo y la revisión de la evidencia; b) la realización de la encuesta y generación de recomendaciones consensuadas. Resultados: han participado un total 95,65% de los centros que actualmente utilizan esta técnica en cáncer de mama y que fueron invitados. Los expertos estuvieron de acuerdo en el uso de RIO exclusiva en cáncer de mama en aquellas pacientes mayores de 60 años y por encima de 50 años posmenopáusicas, con carcinoma ductal infiltrante o subtipos histológicos favorables, sin invasión linfovascular, tumores menores o iguales a 25 mm, márgenes de resección libres y receptores hormonales positivos. La utilización de RIO como rescate de recidiva local después de la irradiación externa alcanzó un nivel de consenso muy fuerte. Conclusión: el presente consenso pretende establecer las guías respecto a las indicaciones de RIO exclusiva o como sobreimpresión anticipada y ser una ayuda para la toma conjunta de decisiones. (AU)

Introduction: The publication of randomized trials with long-term results has demonstrated that intraoperative radiation therapy (IORT) in early-stage breast cancer can be a therapeutic alternative for well-selected cases. This paper present work presents the results of the first multidisciplinary consensus on IORT in breast cancer carried out in Spain. Materials and methods: A systematic literature review was conducted, and all radiation oncologists and surgeons with expertise in IORT for breast cancer in Spain were invited to participate in the consensus. The following methodology was employed in two phases: a) creation of a working group and review of the evidence; b) conduct of the survey and generation of consensus recommendations. Results: A total of 95.65% of the invited centers currently utilizing this technique in breast cancer participated. The experts agreed on the use of exclusive intraoperative radiation therapy in breast cancer for patients above 60 years of age and above 50 years postmenopausal, with invasive ductal carcinoma or favorable histological subtypes, no lymphovascular invasion, tumors less than or equal to 25 mm, clear surgical margins, and positive hormone receptor. The use of IORT as salvage surgery for local recurrence after external irradiation achieved a very strong consensus level. Conclusion: The present consensus aims to establish guidelines regarding the indications for exclusive IORT or as an early boost, and to serve as an aid for joint decision-making. (AU)

Respuesta biológica en las pacientes con cáncer de mama tratadas con radioterapia intraoperatoria / Biological response in breast cancer patients using intraoperative radiotherapy

Introducción: el tratamiento conservador de la mama junto con la radioterapia es de elección en las pacientes con cáncer de mama precoz. Gracias a un mayor conocimiento de la radiobiología tumoral, la tendencia actual consiste en utilizar técnicas de irradiación parcial acelerada, entre las que destaca la radioterapia intraoperatoria (RIO). Métodos: estudio prospectivo multicéntrico dividido en 2 grupos comparativos con casos consecutivos de las pacientes a que han recibido una cirugía conservadora por cáncer de mama asociada o no a RIO. Se valora la relación de esta terapia con los valores de las proteínas involucradas en la respuesta biológica (IL6, IL8, CXCL10, IL1β y TNF- α) en muestras de suero preoperatorio y a las 24 h desde la cirugía, y de drenaje quirúrgico a las 6 y 24 h desde la cirugía. Resultados: se ha objetivado en las pacientes tratadas con RIO una disminución significativa de IL6 e IL8, así como un aumento de CXCL10 favorable para la lucha contra la progresión del tumor (p valor < 0,05). Las alteraciones del sistema inmunológico se manifiestan tanto en suero como en débito del drenaje quirúrgico a las 6 y 24 h desde la cirugía. Conclusiones: la RIO modifica la respuesta biológica en las pacientes con cáncer de mama. A pesar de que se deben desarrollar más líneas de investigación, la comprensión de los mecanismos de desarrollo del tumor, abre una nueva etapa en el desarrollo de tratamientos perioperatorios dirigidos a dianas concretas que compensen las consecuencias dañinas de la cirugía. (AU)

Introduction: Breast conserving surgery with radiotherapy is the treatment of choice in patients with early breast cancer. Due to a better understanding of tumour radiobiology, the current trend is to use accelerated partial irradiation techniques, among which intraoperative radiotherapy (RIO) stands out. Methods: Prospective multicentre study divided into two comparative groups with consecutive cases of patients who have undergone conservative surgery for breast cancer associated or not with RIO. The relation of this therapy with the values of proteins involved in the biological response (IL6, IL8, CXCL10, IL1β y TNF- α) is assessed in serum samples preoperative and 24 hours after surgery, and surgical drainage samples at 6 and 24 hours after surgery. Results: A significant decrease in IL6 and IL8, as well as an increase in CXCL10 favourable for the fight against tumour progression (p-value < 0.05) was observed in patients treated with RIO. Immune system alterations are manifested in both serum and surgical drainage debit at 6 and 24 hours after surgery. Conclusions: RIO modifies the biological response in breast cancer patients. Although more lines of research need to be developed, the understanding of the mechanisms of tumour development opens a new stage in the development of perioperative treatments directed at specific targets that compensate for the harmful consequences of surgery. (AU)

Radioterapia intraoperatória com elétrons no tratamento do câncer colorretal localmente avançado submetido a ressecção incompleta: análise econômica sob a perspectiva do Sistema de Saúde Suplementar brasileiro / Intraoperative electron-beam radiotherapy in locally advanced rectal cancer, in patients submitted to suboptimal surgery: economic analysis on the Brazilian Private Health Care system perspective

Objetivo: Este estudo objetivou avaliar o custo-efetividade da aplicação da radioterapia intraoperatória com elétrons (RIOe) no paciente com câncer retal localmente avançado (CRLA) submetido a radio/quimioterapia neoadjuvante seguida de ressecção incompleta (margem comprometida ou doença grosseira residual). Métodos: Para tanto, foi elaborado um modelo de Markov. Os dados de eficácia, efeitos secundários, controle local e sobrevida global foram extraídos da literatura. A perspectiva considerada foi a do sistema de saúde privado brasileiro. Considerou-se, para o custo e para a efetividade, uma taxa de desconto anual de 5%. Resultados: A estratégia que continha a RIOe mostrou-se, nesse cenário, dominante em comparação à estratégia que não envolvia essa abordagem. Os resultados mostraram-se robustos após análises de sensibilidade uni e multivariadas. Conclusão: Concluiu-se que pode ser vantajosa, tanto para os pacientes com CRLA quanto para as operadoras de saúde do mercado privado brasileiro, a aplicação de RIOe na ocorrência de cirurgia subótima, ainda que se sugira que esses dados devem ser confirmados posteriormente, por meio da coleta de dados de mundo real, devido à ausência de níveis robustos de evidência, na literatura, para esse cenário clínico específico.

Objective: This study aimed to evaluate the cost-effectiveness of intraoperative electron radiotherapy (IOeRT) in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant radio-chemotherapy, followed by incomplete resection (compromised margin or gross residual disease). Methods: A Markov model was constructed. Data on efficacy, side effects, local control and overall survival were extracted from the literature. The perspective was that of the Brazilian private health system. For the cost and effectiveness, an annual discount rate of 5% was considered. Results: The strategy that contained IOeRT was, in this scenario, dominant, in comparison to standard of care. Results were considered robust, after univariate and multivariate sensitivity analyzes. Conclusions: We concluded that it can be advantageous, both for patients with LARC submitted to suboptimal surgery, as well as for Brazilian health insurance companies, the application of IOeRT. Although it is suggested that these results should be confirmed later, through the collection of real-world data, due to the absence of randomized controlled trials, in this specific clinical scenario.

Breast-conserving surgery in breast cancer and intraoperative radiotherapy. Can we predict the fibrosis? / Cirugía conservadora de cáncer de mama y radioterapia intraoperatoria. ¿Podemos predecir la fibrosis?

INTRODUCTION: Radiotherapy techniques associated with breast-conserving surgery have evolved in early breast cancer thanks to a better knowledge of tumor radiobiology, highlighting intraoperative radiotherapy (IORT). However, complications have been documented with this procedure, mainly fibrosis. Transforming growth factor beta (TGF-ß) is a cytokine with an active role in radiation-induced fibrosis, which could be used as an early biomarker for the development of fibrosis. METHODS: Multicentric prospective analysis of 60 patients with breast cancer who underwent breast-conserving surgery, 30 of whom had received additional IORT. TGF-ß values were evaluated in serum pre-surgery and in serum collected 24h after surgery. In addition, we evaluated surgical wound fluids collected 6h and 24h following surgery. RESULTS: Serum and surgical wound fluids TGF-ß values collected over 24h following surgery were significantly higher in patients who received additional IORT (P<.0001). Notably, 8 of these patients showed values above 1,000pg/ml. There were no differences between the samples (serum or surgical wound fluids) (P=.5881). CONCLUSIONS: Although further investigation is needed, higher TGF-ß values in IORT during breast-conserving surgery can be used as an early biomarker for the development of fibrosis.

Radioterapia intraoperatória com elétrons no tratamento do câncer de mama inicial ­ revisão bibliográfica e análise econômica / Intraoperative electron beam radiation-therapy for early breast cancer ­ bibliographic review and economic analysis

Objetivos: Comparar os resultados de controle local e sobrevida global e fazer uma análise econômica comparativa da radioterapia intraoperatória com elétrons (IOeRT) para o tratamento da neoplasia de mama inicial, em comparação à radioterapia conformacional de toda a mama (RT 3D). Métodos: Foi feita revisão sistemática da literatura e, posteriormente, considerando-se os resultados comparáveis de eficácia, análise de minimização de custos, comparando as técnicas mencionadas anteriormente. Resultados: Foi incluído um estudo randomizado. Observou-se pequeno aumento do número de falhas locais em cinco anos (4,4 vs. 0,4%), sem alteração, porém, na sobrevida global. Quando se restringiu o estudo às mulheres com tumores de até 2,0 cm de diâmetro, grau I ou II, com axila negativa ou com até três linfonodos comprometidos e com tumores não classificados como triplos-negativos, chegou-se a um nível comparável de controle local (1,5% de recidivas em cinco anos), sem diferenças significativas no tocante aos efeitos secundários ao tratamento. Em análise econômica posterior, optou-se, então, pelo estudo de minimização de custos, sob a perspectiva das operadoras de saúde do sistema de saúde privado brasileiro, tendo como base os custos dos procedimentos descritos na Classificação Brasileira Hierarquizada de Procedimentos Médicos (CBHPM), 5ª edição. Nesta análise, observou-se que a aplicação da IOeRT implica uma economia de recursos da ordem de 51,5% por tratamento. Conclusão: Conclui-se que a IOeRT é opção que leva à economia de recursos quando utilizada no tratamento de mulheres com câncer de mama inicial, sob a perspectiva das operadoras de saúde do Brasil, quando observados os critérios de inclusão descritos previamente.

Objectives: To compare local control and overall survival and perform an economic analysis between intraoperative electron beam radiation therapy (IOeRT) and conformal radiotherapy, directed to the whole breast (RT 3D), for the treatment of early breast cancer. Methods: A systematic review of the literature was performed, with the inclusion of 1 controlled randomized study, comparing IOeRT with standard treatment ­ RT 3D, in early breast cancer. Posteriorly, due to comparable results between the studied techniques, a cost-minimization analysis was executed. Results: There was a small increase in the number of local failures, in 5 years (4.4 vs. 0.4%), but with no changes in overall survival. When the analysis was restricted to women with tumors up to 2.0 cm, grades I or II, with negative axilla or with up to 3 compromised lymph nodes and with tumors not classified as triple-negative, a comparable level of local control was reached (1.5% over 5 years), without significant differences in treatment side effects. In the following economic analysis, a cost minimization study was chosen, once both treatments were equivalent, considering local control and overall survival. The perspective was that of the Brazilian private healthcare system, based on the costs of the procedures according to the Brazilian Hierarchical Classification of Medical Procedures (CBHPM), 5th edition. In this analysis, it was observed that the delivery of IOeRT implies a resource saving of 51.5% per treatment. Conclusion: We conclude that IOeRT is a very interesting option, that leads to resource savings, when used in the treatment of women with early breast cancer, observing the inclusion criteria previously described, in the Brazilian health care payer's perspective.

Intraoperative radiotherapy with the Intrabeam® device for the treatment of resectable pancreatic adenocarcinoma. / Radioterapia intraoperatoria con Intrabeam® para el tratamiento del adenocarcinoma de páncreas resecable.

INTRODUCTION: The application of intraoperative radiation therapy to the tumor bed after resection of pancreatic cancer has been shown to be beneficial in the local control of the disease. The objective of this study was to evaluate the preliminary outcomes after the application of a single intraoperative dose to the tumor bed with a new intraoperative radiotherapy device (Intrabeam®) in terms of viability, safety and short-term results. METHODS: We studied 5 patients who underwent pancreaticoduodenectomy for resectable pancreatic cancer in which a radiotherapy boost (5Gy) was intraoperatively applied to the tumoral bed using the portable Intrabeam® device, a low-energy point-source X-ray. Postoperative complications, hospital stay and mortality, recurrences and short-term survival were analyzed. RESULTS: Mean patient age was 68 years. All patients had a T3-stage tumor and one of them N1. In 3 patients, R0 resection was performed, while R1 resection was conducted in 2. Perioperative mortality was 0%. The only complications included delayed gastric emptying and postoperative hemorrhage. There were no pancreatic fistulas. During follow-up (mean: 11.2 months), there was a relapse in the patient who had undergone R1 resection. CONCLUSIONS: The application of radiotherapy with the Intrabeam® device in selected patients has not resulted in increased perioperative morbidity or mortality; therefore, this is a safe procedure for the treatment of resectable cancer.

Pioderma gangrenoso após quadrantectomia de mama com radioterapia intraoperatória: relato de caso / Pyoderma gangrenosum after quadrantectomy with intraoperative radiotherapy: a case report

Pioderma gangrenoso é uma doença inflamatória imunomediada e rara da pele, de diagnóstico extremamente desafiador. A evolução clínica é a base para o diagnóstico, cursando com lesões pustulosas superficiais, halo eritematoso doloroso, rápida progressão para ulcerações dolorosas e estéreis, sem resposta a antibióticos ou a novas intervenções cirúrgicas e, finalmente, com pronta melhora com uso de imunossupressores. O atraso no diagnóstico pode acarretar numerosas internações e terapias prolongadas, sendo que seu reconhecimento precoce, por outro lado, evita a progressão dessas ulcerações e sua morbidade. Relatou-se um caso de pioderma gangrenoso que evoluiu após cirurgia associada à radioterapia intraoperatória no tratamento conservador do câncer de mama, fazendo-se uma revisão de casos relatados na literatura e suas possibilidades terapêuticas. Questiona-se, também, se a radioterapia intraoperatória estaria relacionada com algum estímulo imunomediado, o que poderia ter facilitado o desencadeamento do quadro.

Pyoderma gangrenosum is an immune-mediated inflammatory and rare skin disease with an extremely challenging diagnosis. The clinical evolution of the disease is the basis for the diagnosis that involves pustular superficial lesions, painful erythematous halo, rapid progression to painful and sterile ulcerations, unresponsiveness to antibiotics or new surgical interventions, and finally, ready improvement with the use of immunosuppressive drugs. Delayed diagnosis may cause numerous hospitalizations and prolonged therapy, whereas early recognition can prevent the progression of the ulcerations and their morbidities. We report a case of pyoderma gangrenosum that evolved after surgery and was associated with intraoperative radiotherapy for the conservative treatment of breast cancer. In addition, we reviewed reported cases in the literature and therapeutic options. It is conjectured that intraoperative radiotherapy might be related to some immune-mediated stimuli that could trigger the clinical condition.