CAROLINA NASCIMBEN MATHEUS
AVALIAÇÃO DO FLUXO SANGUÍNEO DO MEMBRO
SUPERIOR DE MULHERES SUBMETIDAS A
ABORDAGEM AXILAR PARA O TRATAMENTO DO
CÂNCER DE MAMA
BLOOD FLOW IN THE SUPERIOR LIMBS OF WOMEN
WITH BREAST CANCER UNDERGOING A SURGICAL
APPROACH TO THE AXILLA
CAMPINAS
2015
UNIVERSIDADE ESTADUAL DE CAMPINAS Faculdade de Ciências Médicas
CAROLINA NASCIMBEN MATHEUS
AVALIAÇÃO DO FLUXO SANGUÍNEO DO MEMBRO
SUPERIOR DE MULHERES SUBMETIDAS A
ABORDAGEM AXILAR PARA O TRATAMENTO DO
CÂNCER DE MAMA
ORIENTADOR: Prof. Dr. LUÍS OTÁVIO ZANATTA SARIAN
BLOOD FLOW IN THE SUPERIOR LIMBS OF WOMEN
WITH BREAST CANCER UNDERGOING A SURGICAL
APPROACH TO THE AXILLA
Tese de Doutorado apresentada ao Programa de Pós-Graduação da Faculdade de Ciências Médicas da Universidade Estadual de Campinas para obtenção do Título de Doutor em Ciências da Saúde, na área de concentração Oncologia Ginecológica e Mamária.
PhD thesis presented to the Medical Sciences Post graduation Program of the School of Medical Sciences of the University of Campinas to obtain the Ph.D grade in Health Sciences in the concentration area of Breast and Gynecologic Oncology
ESTE EXEMPLAR CORRESPONDE À VERSÃO FINAL DA TESE DEFENDIDA PELA ALUNA CAROLINA NASCIMBEN MATHEUS
E ORIENTADA PELO Prof. Dr. LUÍS OTAVIO ZANATTA SARIAN
Assinatura do Orientador
Ficha catalográfica
Universidade Estadual de Campinas Biblioteca da Faculdade de Ciências Médicas
Maristella Soares dos Santos – CBB 8/8402
Informações para Biblioteca Digital
Título em outro idioma: Blood flow in the superior limbs of women with breast cancer undergoing a surgical approach to the axilla
Palavras-chave em inglês:
Breast cancer
Lymph node dissection Sentinel lymph node biopsy Blood circulation
Ultrasonography
Área de concentração: Oncologia Ginecológica e Mamária
Titulação: Doutor em Ciências da Saúde
Banca examinadora:
Luís Otavio Zanatta Sarian [Orientador] Cássio Cardoso Filho
César Cabello dos Santos Gil Facina
Gilberto Uemura
Data da defesa: 23-07-2015
Programa de Pós-Graduação: Tocoginecologia
Nascimben Matheus, Carolina, 1980-
M421a Avaliação do fluxo sanguíneo do membro superior de mulheres submetidas a abordagem axilar para tratamento do câncer de mama / Carolina Nascimben Matheus. – Campinas, SP : [s.n.], 2015.
Orientador: Luís Otávio Zanatta Sarian.
Tese (Doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas.
1. Neoplasias da mama. 2. Excisão de linfonodo. 3. Biópsia do linfonodo sentinela. 4. Circulação sanguínea. 5. Ultrassonografia. I. Sarian, Luís Otávio Zanatta, 1974-. II. Universidade Estadual de Campinas. Faculdade de Ciências Médicas. III. Título.
BANCA EXAMINADORA DA TESE DE DOUTORADO
Aluna: CAROLINA NASCIMBEN MATHEUS
Orientador: Prof. Dr. LUÍS OTAVIO ZANATTA SARIAN
Membros:
1. Luís Otavio Zanatta Sarian
2. Cássio Cardoso Filho
3. César Cabello dos Santos
4. Gil Facina
5. Gilberto Uemura
Curso de Pós-Graduação em Tocoginecologia da Faculdade de Ciências Médicas da Universidade Estadual de Campinas
Resumo
Objetivo: Esta tese visou avaliar os parâmetros vasculares arteriais e
venosos dos vasos axilares e braquiais em mulheres submetidas a tratamento para câncer de mama. Subdividimos estas avaliações conforme os objetivos abordados em duas publicações, respectivamente: 1) Comparar aos parâmetros de circulação venosa e arterial nos vasos axilares e braquiais em função do tipo de abordagem cirúrgica da axila (BLS ou LAT) em até seis meses após a intervenção. 2) Identificar os fatores que influenciam os parâmetros vasculares da veias axilares e braquiais ipsilaterais à cirurgia para tratamento do câncer de mama. Métodos: Foram identificadas 547 pacientes consecutivas, submetidas a tratamento cirúrgico para câncer de mama entre agosto de 2012 e janeiro de 2014. Depois de seguir critérios de inclusão e exclusão, 197 mulheres foram recrutadas. O projeto foi aprovado pelo comitê de ética do hospital e todos os pacientes assinaram o termo de consentimento informado. Os critérios de inclusão foram 1) câncer da mama primário operável 2) abordagem axilar cirúrgica; 3) não ter sido submetida a reconstrução da mama. Os critérios de exclusão foram 1) câncer de mama bilateral, 2) história prévia de procedimentos cirúrgicos para um dos membros superiores ou no tórax, 3) comprometimento ortopédico ou neurológico de um dos membros superiores, 4) insuficiência renal ou cardíaca. Todas as pacientes responderam a um breve questionário sobre suas características clínicas e epidemiológicas. Foi então realizada avaliação ultrassonográfica dos vasos braquiais e axilares, bilateralmente, nos seguintes momentos: no dia anterior à cirurgia e 1, 3, 6 e 12 meses após a cirurgia. No primeiro artigo, comparamos os parâmetros arteriais e venosos, até seis meses após a cirurgia, em função da realização da
dissecção linfática completa ou linfonodo sentinela; no segundo, restringimos as análises ao sistema venoso e estendemos a avaliação para até 1 ano após a cirurgia, comparando os parâmetros vasculares em função de características clínicas e epidemiológicas das pacientes e das modalidades de tratamentos utilizados. Resultados: Foram encontradas restrições de diâmetro em veias do braço ipsilateral ao câncer de mama de mulheres submetidas à dissecção axilar (LAT), efeito que não foi observado no grupo BLS. A área da secção transversal de veias braquial e axilar diminuiu progressivamente até seis meses, com a redução do fluxo sanguíneo concomitante destes vasos. Encontramos, na mulher sem linfedema, que a área de secção transversal e fluxo venoso do sangue (especialmente veia braquial) são negativamente afetados pela cirurgia e / ou quimioterapia / radioterapia. Este efeito prejudicial parece persistir até um ano. Não houve diferença significativa em nenhum dos parâmetros estudados entre os vasos ipsi e contralaterais ao câncer de mama. Conclusões: De maneira geral, nosso estudo demonstra que os tratamentos cirúrgicos, especialmente LAT, e a radio e quimioterapia, possuem efeitos deletérios sobre a circulação sanguínea dos vasos axilares e braquiais, sobretudo venosos. Esses efeitos são aparentemente permanentes e há necessidade de extensão do tempo de follow-up a fim de avaliar se o desenvolvimento subsequente de linfedema ocorrerá em associação às alterações vasculares.
Palavras-chave: neoplasias da mama, excisão de linfonodo, biópsia do
linfonodo sentinela, circulação sanguínea, ultrassonografia, velocidade do fluxo sanguíneo.
Abstract
Objective: The aim of this thesis was to evaluate the arterial and venous
vascular parameters of the axillary and brachial vessels in women who underwent treatment for breast cancer. We subdivided these assessments according to the following objectives, in two publications: 1) To compare the venous and arterial vascular parameters in the axillary vessels and brachial depending on the type of axillary surgical approach (SLNB or ALND) within six months after the intervention. 2) To identify which factors influence the vascular parameters of axillary and brachial veins ipsilateral to surgical for treatment of breast cancer. Methods: We identified 547 consecutive patients undergoing surgical treatment for breast cancer between August 2012 and January 2014. After following inclusion and exclusion criteria, 197 women were recruited. The project was approved by the hospital's ethics committee and all patients signed an informed consent form. Inclusion criteria were 1) primary operable breast cancer 2) surgical axillary approach; 3) not having undergone breast reconstruction. Exclusion criteria were 1) bilateral breast cancer, 2) history of previous surgical procedures for one of the upper limbs or breast, 3) orthopedic or neurological impairment of one upper limb, 4) kidney or heart failure. All patients completed a brief questionnaire about their clinical and epidemiological characteristics. Then we performed Doppler ultrasonography evaluation of axillary and brachial vessels, bilaterally, at the following times: the day before surgery and 1, 3, 6 and 12 months after surgery. In the first article, we compared the arterial and venous parameters, up to six months after surgery, depending on SLNB or ALND; in the second, we restricted the analysis to the venous system and extend the evaluation for up to 1 year after surgery, comparing the
vascular parameters with clinical and epidemiological characteristics of patients and treatment modalities used. Results: diameter restrictions were found in the ipsilateral veins of the arm in women with breast cancer undergoing ALND, and that effect was not observed in SLNB group. The cross sectional area of brachial and axillary veins progressively decreased up to six months, with concomitant reduction of blood flow to these vessels. In women with no lymphedema, the cross-sectional area and venous blood flow (especially brachial vein) are negatively affected by surgery and / or chemotherapy / radiotherapy. This detrimental effect seems to persist up to one year. There was no significant difference on studied parameters between ipsilateral and contralateral vessels to breast cancer. Conclusions: In essence, our study shows that surgical treatments, especially ALND, and the radiation and chemotherapy, have deleterious effects on blood circulation of the axillary and brachial vessels, especially venous. These effects are apparently permanent, prompting the extension of the follow-up evaluation in order to assess whether subsequent lymphedema formation will be associated with vascular abnormalities.
Keywords: breast cancer, lymph node excision, sentinel lymph node biopsy,
Sumário
Dedicatória...xiii
Agradecimentos...xv
Símbolos, Siglas e Abreviaturas...xiii
1. Introdução ... 1 1.1. Justificativa ... 7 2. Objetivos ... 9 2.1. Objetivo Geral ... 9 2.2. Objetivos Específicos ... 9 3. Publicações ... 10 Artigo 1 ... 11 Artigo 2 ... 35 4. Discussão ... 59 5. Conclusões... 66 6. Referências ... 67 7. Anexos ... 73
7.1. Anexo 1 – Check List ... 73
7.2. Anexo 2 – Ficha para coleta de dados ... 74
7.3. Anexo 3 – Carta de aprovação do projeto CP – DTG/FCM/UNICAMP ... 77
7.4. Anexo 4 – Carta de aprovação do projeto no CEP – FCM/UNICAMP ... 78
Dedico este trabalho...
Agradecimentos
A Deus, por embasar os princípios e valores de minha vida.
Ao meu esposo Alexandre, amado, amigo e incentivador de todo meu aprimoramento profissional.
Aos meus pais, Eliana e Antônio Carlos, pelo amor incondicional e pelo cuidado ofertado à minha família nos momentos de meus estudos. Estendo a minha sogra Márcia, semelhante reconhecimento.
Ao Prof. Dr. Luís Otávio Zanatta Sarian, pela sua cumplicidade e responsabilidade na orientação e construção desta tese. A você, minha admiração e respeito.
Ao Prof. Dr. Rodrigo Menezes Jales, pela parceria, disponibilidade e paciência nos ensinamentos ecográficos.
A minha companheira Cintia Furlan, amiga fiel e pesquisadora exemplar, por auxiliar-me em todas as atribulações vivenciadas nos últimos anos. Seu apoio pessoal e profissional foi incomensurável e inesquecível.
Aos Professores César Cabello dos Santos e Cássio Cardoso Filho, pelas valiosas sugestões durante o processo de qualificação.
A todas as mulheres, que apesar de estarem em meio aos infortúnios decorrentes do câncer mamário, se voluntariaram a este estudo.
A todos os profissionais do Setor de Ecografia, da Enfermaria da Oncologia e do Ambulatório de Mama.
As queridas Carla Silveira e Carla Andreucci Polido, pela amizade e exemplo.
Aos professores e funcionários do Programa de Pós-Graduação em Tocoginecologia – Unicamp, pelo exímio trabalho.
As secretárias da Oncologia, Neusa, Débora e Sônia, pelo auxílio e pelos agradáveis momentos.
A toda a equipe multiprofissional do DTG-CAISM – UNICAMP.
A cada um que tenha direcionado a mim qualquer auxílio ou desejo de sucesso nesse período.
Símbolos, Siglas e Abreviaturas
A
BLS / SLNB
– cross-sectional area
– Biópsia do Linfonodo Sentinela / Sentinel Lymph Node Biopsy
BMI – Body Mass Index
cm cm2
– centimeters
– square centimeters
cm/s – centimeters per second
d2 ER
– vessel diameter
– Estrogen Receptor
et al. – e outro(s); e outra(s)
Her2
HM-CAISM
– Human Epidermal growth factor Receptor 2
– Hospital da Mulher Prof.Dr. José Aristodemo Pinotti -Centro de Atenção Integral à Saúde da Mulher
LAT / ALND – Linfonodectomia Axilar Total / Axillary Lymph Node Dissection
MHz – megahertz
ml/min – mililiters per minute
p – p-value
SD – Standard Desviation
UNICAMP US
– Universidade Estadual de Campinas
Este estudo foi financiado:
A pesquisadora principal recebeu bolsa de doutoramento da Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES.
"A verdadeira viagem de descobrimento não consiste em procurar novas paisagens,
mas em ter novos olhos."
1. Introdução
Anualmente, mais de um milhão e seiscentas mil mulheres são diagnosticadas com câncer de mama em todo o mundo (1). Não obstante os esforços para o rastreamento e diagnóstico precoce, esse tipo de câncer ainda é a maior causa de morte por câncer nas mulheres. No Brasil, em 2014, foram estimados 57.120 casos novos da neoplasia, com abalo importante à saúde e à economia do país (2).
A busca pelo aumento da sobrevida nos casos de câncer mamário não encerra as responsabilidades e cuidados da equipe de saúde. Afastar as mulheres do risco de óbito sem ofertar assistência às mazelas decorrentes do tratamento dessa neoplasia não assegura o bem-estar das mesmas (3). Neste contexto, esta tese contribui com o estudo dos ajustes fisiopatológicos advindos das intervenções para tratamento do câncer de mama.
O tratamento dessa neoplasia se inicia com o estadiamento do câncer de mama e consequente definição do tipo de abordagem a ser realizada, se neoadjuvância ou cirurgia. Quando se opta por iniciar o tratamento pela
abordagem cirúrgica, há essencialmente duas opções: o tratamento conservador ou radical (3,4). Independentemente da radicalidade da abordagem cirúrgica da mama, sempre se faz necessária a avaliação dos linfonodos da axila, a fim de determinar o acometimento das cadeias de linfonodos axilares por neoplasia e, por fim, estadiar a doença. Em essência, há duas opções de abordagem axilar à disposição dos cirurgiões: a biópsia do linfonodo sentinela (BLS), e a linfonodectomia axilar total (LAT) (3,4).
A BLS é considerada menos agressiva que a LAT, sobretudo em decorrência da menor ocorrência de linfedema nos períodos pós-operatórios, embora esta sequela possa ocorrer em ambos os casos (5,6). Dor, limitação de movimentos do ombro, distúrbios sensoriais, seroma e infecção são outras complicações associadas, em maior ou menor grau, à BLS ou LAT (7,8).
Em decorrência da intensa interdependência anatômica e funcional entre os sistemas linfático e sanguíneo, as intervenções que afetem o sistema linfático podem também produzir alterações no fluxo sanguíneo arterial e venoso (9,10). Tecnicamente, as dissecções axilares, sobretudo a LAT, são dificultadas pela presença de importantes vasos sanguíneos, os quais estão em íntima relação anatômica com os linfonodos, objetos de tais dissecções. As artérias e veias axilares e subclávias são amplamente manipuladas na LAT, o que, em tese, pode acarretar alterações de sua morfologia com possíveis implicações funcionais sobre a dinâmica do fluxo sanguíneo (11,12).
O próprio linfedema decorrente da interrupção dos vasos linfáticos pode, por alterações pressóricas e osmóticas do entorno vascular arterial e venoso,
modificar a pré e pós-carga e desta feita afetar a dinâmica de fluxo. Todavia, o desconhecimento prevalece na literatura envolvendo 1) a intensidade de tais possíveis alterações; 2) os fatores associados a essas mudanças. Outra questão ainda não abordada adequadamente pela ciência refere-se ao momento do pós-operatório em que as possíveis modificações do fluxo sanguíneo ocorrem e, sobretudo, se tais alterações teriam implicações clínicas relevantes.
O método mais utilizado atualmente para avaliação do fluxo sanguíneo e de outros parâmetros vasculares é a ultrassonografia Doppler. A ferramenta Doppler associada à ultrassonografia convencional demonstra em tempo real a arquitetura vascular e os aspectos hemodinâmicos dos vasos em diversos órgãos. Através desse método, pode-se avaliar o movimento do sangue no sistema cardiovascular [13].
O Efeito Doppler, na física, ocorre quando ondas são emitidas ou refletidas por um objeto que se movimenta em relação ao observador. Ondas emitidas por objetos estáticos se propagam em todas as direções de maneira uniforme, mas quando há movimento da fonte de onda, a frequência dessas ondas diminui ou aumenta na percepção do observador. No exame de ultrassom Doppler, o transdutor funciona como fonte fixa, emissora e receptora das ondas refletidas pelas hemácias, as quais estão em contínua movimentação. Como, matematicamente, a variação da freqüência é diretamente proporcional à velocidade de aproximação ou de afastamento, o equipamento consegue calcular a velocidade do sangue durante o exame. A
velocidade do sangue representa a distância percorrida pelas células num determinado tempo. Na presença de estenose (diminuição do diâmetro do vaso), há um aumento na velocidade do sangue. Quando há redução importante do calibre do vaso pode haver também redução do fluxo sanguíneo, (volume de sangue transportado) [14].
Os resultados de estudos utilizando ultrassonografia Doppler, analisando algumas questões levantadas anteriormente ainda são incipientes e, eventualmente, conflitantes. Previamente, em nosso estudo realizado em mulheres que se submeteram à linfonodectomia axilar para tratamento do câncer de mama, sem linfedema, identificamos aumento significativo na velocidade sanguínea (arterial e venosa) dos vasos axilares e braquiais do membro superior homolateral à cirurgia. Sugerimos, como justificativa, a presença de uma possível estenose vascular decorrente principalmente da remoção dos linfonodos e da realização da radioterapia [15].
Estudos anteriores revelaram alterações venosas e arteriais em mulheres mastectomizadas com linfedema [16,17] além da influência de predisposição para desenvolvimento dessa morbidade [18]. Assim, indícios apontam que não só a função deteriorada do sistema linfático, mas também possíveis mudanças no fluxo sanguíneo e na filtração vascular venham favorecer o surgimento do linfedema.
Outros autores relacionam o esvaziamento dos linfonodos axilares com bloqueio do fluxo linfático, estenose da veia axilar, diminuição das conexões
linfovenosas, estase sanguínea e hipercoagulabilidade do sangue venoso [19-21].
Como pode se inferir dos argumentos acima, a literatura constata uma complexidade de fatores envolvidos com as modificações do fluxo sanguíneo nesse período, associada às condições clínicas e funcionais das mulheres acometidas, principalmente no que se refere aos efeitos imediatos e tardios dessa cirurgia.
Por muitas vezes, o foco das pesquisas vasculares foi e continua sendo o estudo do linfedema. Svensson et al. [16,17], por exemplo, observando mulheres mastectomizadas com e sem linfedema, sugeriu que a formação de tal complicação não decorre do bloqueio linfático como um evento isolado, posto que, por meio do ultrassom Doppler, detectou a presença de alterações tanto venosas quanto arteriais nos casos de linfedema.
Entretanto, diversos achados direcionam para a presença de ajustes circulatórios pós tratamento do câncer de mama, independente do desenvolvimento do linfedema. Stanton et al. [18], procurando justificativas para o desenvolvimento do linfedema em mulheres que realizaram BLS e cirurgias menos agressivas, e para o não desenvolvimento do linfedema em mulheres com LAT e cirurgias radicais, apontaram que fatores predisponentes (como anormalidades circulatórias) podem favorecer o desenvolvimento do mesmo. Estes autores sugerem é necessário considerar possíveis mudanças no fluxo sanguíneo e na filtração vascular para compreender as características dessas
mulheres, e não somente considerar a função deturpada do sistema linfático decorrente do procedimento cirúrgico.
Há mais de 40 anos pesquisadores [22,23] já identificavam e tentavam compreender o aparecimento de shunts linfovenosos. Esses estudiosos sugeriram que condições patológicas, como o câncer, poderiam formar essas conexões entre o sistema linfático e o sistema venoso, independente da realização de cirurgia e/ou linfadenectomia.
Aboul-Enein et al. [19] observaram, por meio de linfangiografia em mulheres mastectomizadas, a existência de conexão anormal linfovenosa entre vasos superficiais no membro superior sem linfedema. Eles demonstraram então, que o aparecimento desses shunts está mais relacionado com o bloqueio do fluxo dos coletores linfáticos decorrentes do esvaziamento axilar do que com a presença de linfedema.
Estenose da veia axilar com fluxo prejudicado foi detectada no estudo de Pain, Vowler e Purushotham [20] tanto nas mulheres que apresentavam linfedema pós mastectomia, como naquelas que não apresentavam tal complicação. Esses autores concluíram, portanto, que o movimento reduzido da parede das veias encontrado nesses casos pode estar relacionado com o esvaziamento axilar da cirurgia, e não com a presença do linfedema.
Autores como Moskovitz et al. [21] identificaram mais alterações venosas decorrentes dos procedimentos cirúrgicos em questão. Ao descrever a fisiopatologia da Síndrome de Web, relataram lesões linfo-venosas, estase sanguínea e hipercoagulabilidade do sangue venoso.
A radioterapia, em adicional, pode modificar e ocasionar prejuízos na vasodilatação endotélio-dependente das artérias expostas à radiação [24]. Assim, as oclusões arteriais e outros eventos vasculares podem ser resultado da redução da biodisponibilidade do óxido nítrico derivado do endotélio ocasionada pela radiação; isso porque o óxido nítrico promove relaxamento do músculo liso da parede do vaso tendo, portanto, ação vasodilatadora [25].
Como pode ser observado na literatura que trata da circulação sanguínea nos casos de linfonodectomia após câncer de mama, constatam-se complexas interações entre eventos, envolvendo a presença de tecido neoplásico, condições predisponentes a vasculopatias, o bloqueio linfático e os efeitos das terapias adjuvantes. Certamente, ainda há que se aprofundar nos estudos relacionados a esse tema, pois ainda existe necessidade de investigação das condições clínicas e funcionais possivelmente associadas aos efeitos imediatos e tardios da linfonodectomia axilar.
1.1. Justificativa
Há questões de relevância clínica a respeito das alterações do fluxo sanguíneo em mulheres submetidas a cirurgias que abordem os linfonodos axilares: é preciso avaliar quando e em que intensidade tais alterações ocorrem, e determinar sua correta etiologia e os fatores associados. Tais questões só serão respondidas se: 1) uma ampla coorte de mulheres for submetida à rigorosa e detalhada avaliação dos diâmetros máximos e dos fluxos arteriais e venosos dos vasos axilares e braquiais antes e depois da
cirurgia, preferencialmente acompanhadas periodicamente por prazo relativamente longo; 2) os fluxos nos membros afetados pela cirurgia forem comparados com aqueles nos membros contra-laterais da mesma mulher; 3) fatores possivelmente associados à alterações de fluxo forem adequadamente controlados: estadiamento da doença, em especial o estado de acometimento neoplásico dos linfonodos, e demais estados mórbidos e características epidemiológicas das doentes.
Esse estudo assim se justifica, pois as avaliações propostas acima permitirão, possivelmente, esclarecer dúvidas a respeito do comportamento temporal do fluxo de importantes vasos do membro superior e os fatores eventualmente associados. Tais informações serão de valia no manejo pós-operatório de pacientes submetidas a dissecções axilares.
2. Objetivos
2.1. Objetivo Geral
Avaliar as alterações circulatórias arteriais e venosas do membro superior de mulheres submetidas à abordagem axilar para tratamento do câncer de mama.
2.2. Objetivos Específicos
Artigo 1: Comparar aos parâmetros de circulação venosa e arterial nos
vasos axilares e braquiais em função do tipo de abordagem cirúrgica da axila (BLS ou LAT) em até seis meses após a intervenção.
Artigo 2: Identificar os fatores que influenciam os parâmetros vasculares da
veias axilares e braquiais ipsilaterais à cirurgia para tratamento do câncer de mama.
3. Publicações
Artigo 1 – Detrimental effects of axillary lymph node dissection on diameter
and blood flow of axillary and brachial veins in patients without lymphedema
Artigo 2 – Surgery, chemo and radiotherapy for breast cancer have
long-lasting anatomical and functional detrimental effects on the axillary and brachial veins: a longitudinal one-year study
3.1. Artigo 1
Detrimental effects of axillary lymph node dissection on diameter and blood flow of axillary and brachial veins in patients without lymphedema
Authors Carolina Nascimben Matheus1,2 Cintia Furlan1,2
Rodrigo Menezes Jales1,3 Sophie FM Derchain1,2 Luís Otávio Sarian1,2
1. Department of Obstetrics and Gynecology, State University of Campinas (Unicamp).
2. Division of Gynecologic and Breast Oncology, Women´s Hospital (CAISM), Unicamp.
3. Radiology Sector, Women´s Hospital (CAISM), Unicamp.
Correspondence to:
Prof. Luís Otávio Sarian,
Campinas State University, Department of Obstetrics and Gynecology, Campinas, Sao Paulo, Brazil.
e-mail: sarian@unicamp.br Telephone: 0 55 19 35219305 Fax: 0 55 19 35219516
Abstract
Purpose. The goal of this study was to compare vascular parameters of the brachial and
axillary arteries and veins in women who underwent Sentinel Lymph Node Biopsy (SLNB) and Axillary Lymph Node Dissection (ALND). Methods. In this prospective study we performed a comprehensive medium-term (up to six months after surgery) evaluation of 155 women divided into two groups: ALND (n=88) and SLNB (n=67). Brachial and axillary arteries and veins in the arm ipsilateral to surgery were imaged by Doppler ultrasound before and 1, 3 and 6 months after surgery. Results. We found ALND diameter restrictions on veins of the arm ipsilateral to the breast cancer, effect that was not observed in the SLNB group. Up to 6 months postoperatively the cross-sectional area of axillary and brachial veins decreased progressively with a concomitant blood flow reduction of these vessels. Conclusion. ALND provides axillary and brachial veins vasoconstriction in arm ipsilateral to breast cancer surgery. Our results attest another aspect of the detrimental effects of ALND to the arm, and also show that SLNB helps avoid these effects.
Keywords: breast cancer, lymph node dissection, sentinel lymph node biopsy, blood
Introduction
Most cases of breast cancer are treated surgically. Sentinel lymph node biopsy (SLNB) or complete axillary lymph node dissection (ALND) are the usual surgical approaches to the axilla ipsilateral to the breast cancer. Since SLNB involves the removal of a small fraction of the axillary lymph nodes, it is considered to entice less morbid consequences to the axilla and ipsilateral arm, such as lymphedema, pain, sensorial disturbances, movement range limitations, seroma formation and infection [1-4]. Other factors that have been shown to be directly associated with upper arm morbidity are the number of compromised nodes [5,6], and the neoadjuvant/adjuvant treatments used [7,8].
Previous studies showed a strong anatomic and functional relationship between the vascular and lymphatic systems. It has also been suggested that interventions affecting the lymphatic system may cause vascular alterations, and vice-versa [9,10]. ALND encompasses the complete removal of lymph nodes surrounding the main vascular supply systems to the upper arms, and substantial manipulation of the axillary arteries and veins is often necessary. It has been suspected that such manipulation may cause anatomic and functional modifications of arm vessels [11]. However, it remains unknown what are the main changes to the upper arm vessels and how long they endure. Several vascular abnormalities have now been described in the vascular structures affected by different forms of lymph node dissection in patients with cancer; however, in general, studies on this subject are cross sectional in nature and have methodological limitations of vascular parameters [12].
In this study, we examined several vascular parameters of the axillary and brachial arteries and veins in women who underwent surgery for the treatment of breast
cancer. We also evaluated the outcomes of these parameters through time (up to six months postoperatively) and thus formed a comprehensive panel of the vascular modifications that can be ascribed to the different types of surgical manipulation of the axilla. The synthesis of this panel is reported here.
Methods
Patient selection
We identified 547 consecutive patients, who underwent surgical treatment for breast cancer between August 2012 and January 2014. After following inclusion and exclusion criteria, 197 women were recruited (Figure 1). We lost to follow up 42 women. The project was approved by the hospital ethical committee and all patients signed the informed consent form. Inclusion criteria consisted of having 1) operable primary breast cancer and which not underwent neoadjuvant chemotherapy, 2) undergone ALND or SLNB, 3) not being submitted to breast reconstructive procedures, since, per institution’s protocol, arm movement restrictions are prescribed to these patients in the first two weeks after surgery. Exclusion criteria comprised 1) bilateral breast cancer, 2) prior history of surgical procedures (not including biopsies for breast cancer diagnosis) to one of the superior limbs or to the breast, 3) orthopedic or neurologic compromise of one of the superior limbs, 4) renal or cardiac insufficiency, and 5) missing more than one sonography evaluations. The final sample size of this study was n= 155 women: 67 who underwent SLNB and 88 ALND.
Assessment
Patients were first approached by the one of the principal investigators (CNM or CF) one day prior to surgery. A brief questionnaire was then applied, covering key clinical and epidemiological aspects such as age, weight and stature, race, years of formal education, profession, smoking habits, and comorbidities. Patient laterality was also logged. Next, the principal investigators proceeded with the Doppler Ultrasound evaluation.
Doppler Ultrasound (Doppler US) evaluation
Exams were performed in a quiet, temperature-controlled (210 to 250), dimly lit room, after resting supine for five minutes [13]. We imaged axillary and brachial arteries and veins, according to scanning techniques proposed by Thrush and Hartshorne [14].
High-resolution ultrasonography of the vessels was performed using a Toshiba Xario XG (Toshiba Medical Systems Corporation, SSA 660, Osaka, Japan) ultrasound machine equipped with a 7.5 MHz linear array probe. The patient was placed in supine position with the head supported on a thin pillow for comfort. The arm was abducted, externally rotated and left on a suitable rest position.
The images were captured from the axilla to the brachial vessels. We evaluated the axillary vessels longitudinally just distal to the axillary-subclavian junction. The distal brachial vessels were evaluated until the elbow, just before the point where it divides in the upper forearm into the radial and ulnar vessels. Imaging of each evaluated vessel was done in both longitudinal and transverse section.
We performed the cross-sectional survey before the longitudinal scan because this helps to relate structures to each other. Longitudinally, the transducer position was
adjusted to obtain optimal images of the near and far walls of the intima. A real-time continuous display of the maximum systolic and minimum diastolic spectral Doppler frequencies was monitored and documented when the values became stable over three consecutive Doppler waveforms. We always selected as small an angle of insonation as possible, not exceeding 60o and properly adjusted the insonation angle to the axis of the vessel.
We assessed Peak Systolic Velocity, End Diastolic Velocity, Mean Flow Velocity, Pulsatility Index (PI) and Resistive Index (RI) in the longitudinal plane of the arteries. PI and IR can be used to quantify the degree of pulse wave damping at different measurement sites. PI is defined as the maximum height of the waveform, S, minus the minimum diastolic, D (which may be negative), divided by the mean height, M , as shown in sequence: PI = S – D / M . The RI is defined as follows: RI = S – E / S , where E is end diastolic velocity. Both IP and IR are calculated by the ultrasonography equipment and displayed on the screen.
Also in the longitudinal plane, we evaluated the Maximum Velocity of the veins. Finally we measured all the vessel diameters (d) in transverse view during the diastole of the cardiac cycle [15]. Cross-sectional area (A) of these vessels and the volume flow of blood (Blood Flow) was calculated as follows [14]:
𝐴 𝑐𝑚2 = 𝜋𝑑 2
4 (𝑐𝑚)
Statistics
We established the following parameters for the calculation of the sample size: alpha error = 5%, beta error = 10%, statistical power = 80% and an estimated difference of 10% in the major blood flow parameters in the vessels of the arm of patients treated with ALND versus that in women who underwent SLNB. The estimated sample size was n = 136 subjects. We first compared the key clinical aspects of the women using chi-squares for categorical data and the Kruskal-Wallis test for continuous data. Next, using the Shapiro-Wilk test, we tested the normality of the distribution of each of the studied blood flow parameters at baseline and during the three rounds of reassessment during follow-up. We then compared the blood flow parameters of each vessel in women who underwent either ALND or SLNB using t-tests for normally distributed data and the Kruskal-Wallis test for non-normally distributed data. We produced iteration graphics of the cross-sectional area and blood flow of the axillary and brachial veins from baseline to 6 months after surgery. The time and group (SLNB versus ALND) effects were evaluated using analysis of variance (ANOVA) for repeated measures. All statistical analyses were performed with the R Environment for Statistical Computing (R Project) [16]. Significance was set at 95% (p=0.05).
Results
Study participants characteristics
The characteristics of the included volunteers are summarized in Table 1, which lists the key features of the women as related to surgical approach to the axilla. Sixty-seven (43%) women were treated with SLNB and 88 (57%) with ALND. Patients’ age, body mass index (BMI), were not associated with the type of surgical treatment given to
the axilla. As per the institution’s treatment protocols, SLNB was restricted to patients with in situ carcinoma up to invasive carcinoma stage II. Patients who were treated with SLNB had a higher proportion of ER-positive (0.04), RP-positive (p=0.01) and her-2 negative tumors (p=0.04) compared to women who were treated with ALND.
Blood flow parameters
Table 2 shows axillary and brachial artery blood flow parameters, from baseline to 6 months after surgery, compared according to the surgical approach to the axilla. The baseline assessment (i.e. prior to surgery) revealed no statistically significant differences in any of the studied parameters, showing that patients who were scheduled to undergo SLNB or ALND had no prior compromise of the studied vessels. Our measurements also revealed that receiving either SLNB or ALND did not interfere with artery blood flow parameters in up to 6 months after surgery.
In Table 3, we compare the axillary and brachial veins blood flow parameters from baseline to up to 6 months after either SLNB or ALND. Baseline parameters were similar for women who were to be treated with SLNB or ALND. Six months after surgery, the axillary and brachial vein cross sectional areas were significantly smaller in women who underwent ALND than in those who underwent SLNB (p<0.001 and p=0.02, respectively). Also, for both axillary and brachial veins, blood flow was significantly slower in women who underwent ALND than in those who underwent SLNB (p<0.001 and p=0.05, respectively).
In figures 2 and 3, respectively, we depict the cross sectional area (A) and blood flow (B) of the axillary and brachial veins from baseline to up to 6 months postoperatively. We observed a significant relationship between the cross sectional area
of the vases and blood flow. In essence, over time, the cross sectional area of both axillary and brachial veins diminished in the ALND group, accompanied by a similar trend in blood flow. These trends were not observable in patients who underwent SLNB. For the axillary vein, we detected a significant (p<0.01) group (ALND vs. SLNB) effect for both the cross sectional area and blood flow. The same was true for the brachial vein, with a significant group-related difference of cross-sectional area (p<0.01) and blood flow (p=0.02) from baseline to up to six months postoperatively.
Discussion
Our study shows that ALND has a negative and persistent effect on the veins of the arm ipsilateral to the breast cancer. ALND was associated with diameter restrictions of these vessels, with a concomitant reduction of blood flow. Importantly, these effects seem to persist, and even get worse, in the 6-month time span covered by this study. Our study also showed that the axillary and brachial arteries are probably more resistant to the effects of ALND as compared to SLNB.
Here we attest another aspect of the detrimental effects of ALND to the arm, and also show that SLNB helps avoid these effects. Our study helps compose the body of evidence that underscores the need for evaluating the oncological safety of replacement procedures, such as SLNB or radiotherapy to the axilla in select cases. A flush of recent trials demonstrated that SLNB is an oncologically safe procedure in many clinical situations where only ALND has been classically accepted. SLNB can replace ALND in women with early-stage disease, with clinically negative axilla [17]. ALND may not be necessary in women with up to two positive lymph nodes who will undergo radiotherapy to the axilla [18]. Lymphadenectomy when micrometastasis is diagnosed in the SLN is
also avoided [19]. However, ALND is still the standard of care in several clinical situations where SLNB is not applicable or when axillary lymph node dissection is mandatory after a positive SLNB [20-26].
We observed a decline in axillary and brachial vein diameter associated with a reduction in blood flow in these vessels. ALND is substantially more aggressive to the anatomic surroundings of these vessels than SLNB. First, ALND encompasses the removal of the lymph nodes revolving axillary and subclavian veins. The removal of these structures is made through electrodissection, which can damage the delicate venous structures and induce the formation of vascular scars [11]. However, it is important to notice that the brachial veins are not directly manipulated during the procedure. We identified a reduction of brachial vein diameter notwithstanding, which suggests that the brachial vein adapts to the modifications directly imposed to the axillary vein. In addition, the axillary vein is at risk for hemorrhagic complications as a consequence of direct injury or thrombosis secondary to surgery traction and/or compression [27].
Lymphatic-venous shunts have been described for a long time in women undergoing ALND [28] and it is sensible to infer that these interactions may play a detrimental role in venous vessel anatomy and functionality. These shunts originate trying to counterbalance lymphatic obstruction and prevent lymphedema [29]. Here, we didn’t analyzed the development of lymphedema, but several studies still detect lymphedema [30,31] in the arm ipsilateral to the ALND or even SLNB.
On the other hand, lymphedema may be itself caused by venous stasis. It has long been demonstrated that fluid leaking to the extravascular space may result from venous hypertension [32,33]. In patients with severe lymphedema, the presence of
visibly distended venous collateral circulation has been demonstrated, venous telangiectasias and delayed emptying of the superficial veins during elevation of the extremity are commons clinical findings [34]. Severe lymphedema to the arm ipsilateral to ALND can thus be a consequence of an abnormal venous flow in the axillary and brachial veins associated with an anatomically damaged lymphatic drainage.
Venous thrombosis, lymphovenous injury, blood stasis and hypercoagulability of venous blood have been described in women who underwent ALND [35]. Pain, Vowler and Purushotham [36] also described axillary vein stenosis in women who underwent ALND. Unfortunately, the incidence of these complications was not examined in women who underwent SLNB.
Generally, most circulatory changes found in studies derive from the comparison between lymphedematous and nonlymphedematous limbs [10]. Differently, in our study we could demonstrate the greatest damage to the venous system in ALND patients compared to that in women who underwent SLNB. Celebioglu et al. [37] measured the skin circulation arms of patients undergoing either SLNB or ALND. They used the laser Doppler technique and no difference was found between then.
In a previous study, we detected an increased flow velocity in the brachial and axillary veins and arteries of women who underwent ALND six months after surgery [38]. However, that study had several technical limitations related to the Doppler US evaluation of the vessels, which we treated in the present study. For instance, we have not measured vessel diameter, preventing us from calculating blood flow. In that study, we hypothesized that blood velocity could had been increased due to a reduction in vessel diameter. Our most recent findings confirmed that hypothesis.
Our study has been designed to cover a six-month time span. However, we noticed that the changes in vessel diameter and blood flow seem to be still ongoing by the end of that period. Unfortunately, we do not have sufficient data to analyze further and determine if and when those trends cease to exist, revert, or even get worse after six months postoperatively. Important, in our previous study [38], we detected blood changes over six months post surgery. On the other hand, our strict patient selection criteria (only 155 women out of 588 triaged were selected for analysis – Figure 1) warrant a homogeneous sample, alongside a comprehensive evaluation of vascular parameters. Importantly, we avoided the inclusion of women who underwent reconstructive breast procedures, warranting a homogeneous sample in terms of surgical extent and comorbidity profile.
As per our institution’s protocol, women undergoing SLNB and ALND shound engage in a one-month physical therapy program.Next, they are prescribed a list of simple exercises to be performed daily, indefinetely. These approaches may be responsible for the improvement of vessel diameter and flow, compared to baseline, six months after surgery in women who underwent SLNB.
In essence, our results clearly shows that ALND is directly associated with diameter and blood flow restrictions of the venous drainage of the arm ipsilateral to surgery. Importantly, these ailments seem to persist or even continually get worse six months after surgery. It has been previously demonstrated that venous stasis may act as a cause or be a consequence of lymphedema. Our study casts some light on the physiopathological consequences of ALND and the protection conferred by SLNB.
Conflict of interest
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Figure 1. STROBE flowchart describing initial dataset and exclusions leading to final
Table 1 – Key features of the women as related to surgical approach to the axilla. Characteristic SLNB ALND p N ( % ) n ( % ) Total of patients 67 88 Age < 55years 31 ( 46.3 ) 46 ( 52.3 ) >55 years 36 ( 53.7 ) 42 ( 47.7 ) 0.56 BMI <24.9 kg/m2 23 ( 34 ) 25 ( 29 ) 25 to 29.9 kg/m2 24 ( 36 ) 32 ( 36 ) 0.56 >30 kg/m2 20 ( 30 ) 31 ( 35 ) Stage 0 (in situ) 6 ( 9 ) 0 ( 0 ) I 30 ( 45 ) 7 ( 8 ) II 31 ( 46 ) 35 ( 40 ) <0.01 III 0 ( 0 ) 45 ( 51 ) IV 0 ( 0 ) 1 ( 1 ) Estrogen receptor Negative 10 ( 15 ) 27 ( 31 ) Positive 57 ( 85 ) 61 ( 69 ) 0.04 Progesterone receptor Negative 14 ( 21 ) 37 ( 42 ) Positive 53 ( 79 ) 51 ( 58 ) 0.01 HER2 Negative 43 ( 71 ) 46 ( 52 ) Positive 18 ( 29 ) 42 ( 48 ) 0.04 Not available 6 ( 10 ) Surgery Conservative 64 ( 95 ) 33 ( 37 ) Radical 3 ( 5 ) 55 ( 63 ) <0.01
SLNB = Sentinel Lymph Node Biopsy; ALND= Axillary Lymph Node Dissection; BMI = Body Mass Index
Table 2– Axillary and brachial artery blood flow parameters from baseline to 6 months after surgery as related to surgical treatment of
the axilla.
Baseline 1 month 3 months 6 months
Peak Systolic Velocity (cm/s) Mean ( SD ) p Mean ( SD ) p Mean ( SD ) p Mean ( SD ) p
Axillary Artery ALND 42.5 ( 14.3 ) 0.5 40.0 ( 13.4 ) 0.8 38.9 ( 13.7 ) 0.5 38.5 ( 13.4 ) 0.9 SLNB 41.5 ( 14.1 ) 39.9 ( 12.9 ) 40.5 ( 12.8 ) 38.2 ( 14.2 ) Brachial Artery ALND 36.5 ( 10.9 ) 0.3 33.0 ( 9.9 ) 0.9 34.7 ( 10.9 ) 0.2 32.5 ( 11.5 ) 0.8 SLNB 34.8 ( 11.4 ) 33.1 ( 11.7 ) 32.2 ( 11.9 ) 32.8 ( 10.1 )
End Diastolic Velocity (cm/s)
Axillary Artery ALND 4.5 ( 5.1 ) 0.2 3.7 ( 3.7 ) 0.6 4.1 ( 3.8 ) 0.9 3.9 ( 3.5 ) 0.9 SLNB 4.8 ( 3.8 ) 3.9 ( 3.2 ) 3.8 ( 3.2 ) 3.7 ( 2.9 ) Brachial Artery ALND 3.9 ( 3.0 ) 0.1 3.2 ( 3.1 ) 0.5 3.7 ( 3.7 ) 0.9 3.5 ( 3.2 ) 0.3 SLNB 4.9 ( 3.7 ) 3.1 ( 2.2 ) 3.3 ( 2.5 ) 3.8 ( 2.7 )
Mean Flow Velocity (cm/s)
Axillary Artery ALND 12.1 ( 5.0 ) 0.8 12.0 ( 5.6 ) 0.4 11.5 ( 4.4 ) 0.8 11.5 ( 4.3 ) 0.6 SLNB 12.1 ( 5.3 ) 11.0 ( 4.2 ) 11.3 ( 3.5 ) 10.8 ( 4.1 ) Brachial Artery ALND 10.2 ( 3.7 ) 0.4 9.7 ( 4.0 ) 0.4 10.3 ( 4.4 ) 0.4 9.6 ( 4.0 ) 0.3 SLNB 10.0 ( 4.3 ) 9.3 ( 3.7 ) 9.5 ( 3.9 ) 9.9 ( 3.3 ) Pulsatility Index Axillary Artery ALND 3.3 ( 0.8 ) 0.5 3.2 ( 0.9 ) 0.6 3.2 ( 0.9 ) 0.1 3.1 ( 0.7 ) 0.2 SLNB 3.2 ( 0.8 ) 3.4 ( 1.1 ) 3.3 ( 0.8 ) 3.1 ( 0.9 )
Brachial Artery ALND 3.4 ( 0.9 ) 0.3 3.3 ( 0.9 ) 0.8 3.3 ( 1.0 ) 0.5 3.1 ( 0.8 ) 0.4 SLNB 3.2 ( 1.0 ) 3.4 ( 1.0 ) 3.1 ( 0.8 ) 3.0 ( 0.7 ) Resistive Index Axillary Artery ALND 0.9 ( 0.1 ) 0.2 0.9 ( 0.1 ) 0.6 0.9 ( 0.1 ) 0.5 0.9 ( 0.1 ) 0.9 SLNB 0.9 ( 0.1 ) 0.9 ( 0.1 ) 0.9 ( 0.1 ) 0.9 ( 0.1 ) Brachial Artery ALND 0.9 ( 0.1 ) 0.4 0.9 ( 0.1 ) 0.6 0.9 ( 0.1 ) 0.6 0.9 ( 0.1 ) 0.4 SLNB 0.9 ( 0.1 ) 0.9 ( 0.1 ) 0.9 ( 0.1 ) 0.9 ( 0.1 ) Cross-sectional area of the vessel (cm2) Axillary Artery ALND 0.16 ( 0.09 ) 0.1 0.14 ( 0.06 ) 0.2 0.15 ( 0.07 ) 0.4 0.15 ( 0.05 ) 0.3 SLNB 0.14 ( 0.05 ) 0.13 ( 0.05 ) 0.15 ( 0.06 ) 0.16 ( 0.04 ) Brachial Artery ALND 0.12 ( 0.03 ) 0.7 0.12 ( 0.04 ) 0.1 0.12 ( 0.04 ) 0.9 0.12 ( 0.04 ) 0.2 SLNB 0.12 ( 0.05 ) 0.11 ( 0.03 ) 0.11 ( 0.04 ) 0.13 ( 0.05 )
Blood Flow (ml/min)
Axillary Artery ALND 103.75 ( 53.38 ) 0.4 108.38 ( 72.63 ) 0.3 108.82 ( 63.91 ) 0.6 101.53 ( 45.18 ) 0.7 SLNB 117.79 ( 80.62 ) 92.02 ( 49.61 ) 102.67 ( 58.99 ) 98.60 ( 40.72 ) Brachial Artery ALND 74.83 ( 36.38 ) 0.5 71.82 ( 38.80 ) 0.3 74.22 ( 44.94 ) 0.6 67.62 ( 30.41 ) 0.2 SLNB 70.10 ( 35.74 ) 62.65 ( 31.78 ) 68.46 ( 37.20 ) 78.96 ( 37.85 )
Table 3 – Axillary and brachial vein blood flow parameters from baseline to 6 months after surgery as related to surgical treatment of
the axilla.
Baseline 1 month 3 months 6 months
Maximum Velocity
(cm/s) Mean ( SD ) p Mean ( SD ) p Mean ( SD ) p Mean ( SD ) p
Axillary Vein ALND 11.4 ( 5.1 ) 0.1 10.6 ( 5.2 ) 0.5 10.8 ( 5.3 ) 0.7 12.2 ( 5.7 ) 0.03* SLNB 10.1 ( 4.0 ) 9.8 ( 4.8 ) 9.9 ( 3.8 ) 10.1 ( 4.2 ) Brachial Vein ALND 10.9 ( 3.9 ) 0.2 10.8 ( 4.6 ) 0.5 11.6 ( 6.8 ) 0.4 10.1 ( 4.6 ) 0.09 SLNB 10.6 ( 5.8 ) 10.0 ( 3.5 ) 10.4 ( 4.9 ) 9.5 ( 3.3 ) Cross-sectional area of the vessel (cm2) Axillary Vein ALND 0.23 ( 0.14 ) 0.6 0.18 ( 0.10 ) 0.6 0.20 ( 0.12 ) 0.3 0.16 ( 0.09 ) <0.001* SLNB 0.21 ( 0.13 ) 0.19 ( 0.09 ) 0.23 ( 0.15 ) 0.28 ( 0.13 ) Brachial Vein ALND 0.10 ( 0.06 ) 0.7 0.09 ( 0.04 ) 0.9 0.08 ( 0.04 ) 0.2 0.07 ( 0.03 ) 0.02* SLNB 0.09 ( 0.04 ) 0.09 ( 0.04 ) 0.10 ( 0.06 ) 0.10 ( 0.05 )
Blood Flow (ml/min)
Axillary Vein ALND 163.50 ( 145.01 ) 0.3 124.09 ( 106.70 ) 0.9 146.26 ( 105.76 ) 0.7 100.12 ( 71.10 ) <0.001* SLNB 126.27 ( 96.72 ) 113.80 ( 74.14 ) 144.14 ( 124.99 ) 165.13 ( 89.67 ) Brachial Vein ALND 72.53 ( 55.90 ) 0.5 59.07 ( 44.99 ) 0.8 56.12 ( 43.41 ) 0.8 45.65 ( 28.58 ) 0.05* SLNB 59.91 ( 36.23 ) 54.50 ( 33.77 ) 56.54 ( 42.06 ) 60.79 ( 38.36 )
(A)
(B)
Figure 2. Cross sectional area (A) and blood flow (B) of the axillary vein from baseline
to up to 6 months postoperatively.
p (group effect) = <0.01 p (group effect) =<0.01
(A)
(B)
Figure 3. Cross sectional area (A) and blood flow (B) of the brachial vein from baseline
to up to 6 months postoperatively.
p (group effect) = <0.01
Artigo 2
Surgery, chemo and radiotherapy for breast cancer have long-lasting anatomical and functional detrimental effects on the axillary and brachial veins: a longitudinal one-year study
Authors Carolina Nascimben Matheus1,2 Cintia Furlan1,2
Rodrigo Menezes Jales1,3 Sophie FM Derchain1,2 Luís Otávio Sarian1,2
1. Department of Obstetrics and Gynecology, State University of Campinas (Unicamp).
2. Division of Gynecologic and Breast Oncology, Women´s Hospital (CAISM), Unicamp.
3. Radiology Sector, Women´s Hospital (CAISM), Unicamp.
Correspondence to:
Prof. LUÍS Otávio Sarian,
Campinas State University, Department of Obstetrics and Gynecology, Campinas, Sao Paulo, Brazil.
e-mail: sarian@unicamp.br Telephone: 0 55 19 35219305 Fax: 0 55 19 35219516
Abstract
Purpose. The goal of this study was to identify the factors that affect vascular
parameters of the axillary and brachial veins of women undergoing surgery for the treatment of breast cancer. Methods. In this prospective study we evaluated 98 women. Brachial and axillary veins in the ipsilateral and contralateral arms to surgery were imaged by Doppler ultrasound in five routines: before the surgery and 1, 3, 6 and 12 months after surgery. We then compared the blood flow parameters of each vessel in upper limb both ipsilateral and contralateral. Comparisons of the blood flow parameters as related to patients’ clinical and epidemiological data were also performed. Results. We found, in woman with no lymphedema, that cross-sectional area and blood venous flow (especially brachial vein) are negatively affected by surgery and/or chemo/radiotherapy. This detrimental effect seems to persist until a year. We also detected no significant difference between ipsi and contralateral side as related to vascular parameters. Conclusion. The extent of surgical approach and adjuvant treatment cause diameter and blood venous flow restrictions in the upper limbs. Our data also underscores the theory that lymphedema is a consequence of vascular ailments.
Introduction
Despite the large number of deaths from breast cancer, fortunately the proportion surviving in five years can reach 80% in early stage (up to IIa) [1]. On the other hand, the morbidities derived from the surgical and adjuvant treatments may be significant and perceived as detrimental to patients’ quality of life [2]. Pain, infection, seroma formation, loss of sensation and lymphedema are commonly post-treatment diagnoses in breast cancer patients [3,4].
It is believed that lymphedema and other arm morbidities may be associated with circulatory abnormalities in the arm ipsilateral to surgery [5] or to radiotherapy [6]. Previous studies suggested that interventions affecting the lymphatic system may cause vascular alterations, and vice-versa [7,8]. The surgical approach to the axilla encompasses the partial or complete removal of lymph nodes surrounding the main vascular supply systems to the upper arms, and substantial manipulation of the axillary arteries and veins is often necessary. It has been suspected that such manipulation may cause anatomic and functional modifications of arm vessels [9]. However, it remains unknown what are the main changes to the upper arm vessels and how long they endure. We performed a comprehensive evaluation of vascular (arterial and venous) parameters in women undergoing surgery for breast cancer. In a previous report, we showed that complete removal of axillary lymph nodes, compared to selective removal of sentinel nodes, is associated with axillary and brachial changes in vein cross-sectional area and blood flow [10]. We also reported that arm arteries are much less sensitive to surgical manipulation, and that vascular parameters seem to be unaffected by surgery in this type of vessel. In the present study, we go further in the study of the vascular
parameters of axillary and brachial veins of women who underwent surgery for the treatment of breast cancer. We evaluated the outcomes of these parameters through time (up to one year postoperatively) and whether disease and patients characteristics may affect these outcomes, thus forming one of more comprehensive panels of the venous vascular modifications that can be ascribed after treatment of breast cancer in the current medical literature.
Methods
Patient selection
We identified 389 consecutive patients, who underwent surgical treatment for breast cancer between August 2012 and August 2014. After following inclusion and exclusion criteria, 140 women were recruited (Figure 1). We lost to follow up 38 women and excluded 4 with arm lymphedema. The project was approved by the hospital ethical committee and all patients signed the informed consent form. Inclusion criteria consisted of having 1) operable primary breast cancer 2) undergone ALND or SLNB, 3) not being submitted to breast reconstructive procedures. Exclusion criteria comprised 1) bilateral breast cancer, 2) prior history of surgical procedures to one of the superior limbs or to the breast, 3) orthopedic or neurologic compromise of one of the superior limbs, 4) renal or cardiac insufficiency, 5) not having undergone one in five sonography evaluation, and 6) lymphedema. The final sample size of this study was n= 98 women.
