THE IMPACT OF NEUROPATHIC PAIN
IN SLEEP QUALITY OF BREAST CANCER PATIENTS
FILIPA FONTES
TESE DE DOUTORAMENTO EM SAÚDE PÚBLICA
APRESENTADA À FACULDADE DE MEDICINA DA UNIVERSIDADE DO PORTO
THE IMPACT OF NEUROPATHIC PAIN
IN SLEEP QUALITY OF BREAST CANCER PATIENTS
FILIPA FERREIRA MAIA FONTES PORTO | 2017
Dissertação de candidatura ao grau de Doutor apresentada à Faculdade de Medicina da Universidade do Porto
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Art.º 48º, § 3º - “A Faculdade não responde pelas doutrinas expendidas na dissertação.” (Regulamento da Faculdade de Medicina da Universidade do Porto – Decreto-Lei nº 19337 de 29 de Janeiro de 1931)
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ATEDRÁTICO DAF
ACULDADE DEM
EDICINA DOP
ORTOProfessores Catedráticos Efetivos
Doutor Manuel Alberto Coimbra Sobrinho Simões Doutora Maria Amélia Duarte Ferreira
Doutor José Agostinho Marques Lopes
Doutor Patrício Manuel Vieira Araújo Soares Silva Doutor Alberto Manuel Barros da Silva
Doutor José Manuel Lopes Teixeira Amarante Doutor José Henrique Dias Pinto de Barros
Doutora Maria Fátima Machado Henriques Carneiro Doutora Isabel Maria Amorim Pereira Ramos
Doutora Deolinda Maria Valente Alves Lima Teixeira Doutora Maria Dulce Cordeiro Madeira
Doutor Altamiro Manuel Rodrigues Costa Pereira Doutor José Carlos Neves da Cunha Areias
Doutor Manuel Jesus Falcão Pestana Vasconcelos
Doutor João Francisco Montenegro Andrade Lima Bernardes Doutora Maria Leonor Martins Soares David
Doutor Rui Manuel Lopes Nunes
Doutor José Eduardo Torres Eckenroth Guimarães Doutor Francisco Fernando Rocha Gonçalves Doutor José Manuel Pereira Dias de Castro Lopes
Doutor António Albino Coelho Marques Abrantes Teixeira Doutor Joaquim Adelino Correia Ferreira Leite Moreira Doutora Raquel Ângela Silva Soares Lino
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Professores Jubilados ou Aposentados Doutor Alexandre Alberto Guerra Sousa Pinto Doutor Álvaro Jerónimo Leal Machado de Aguiar Doutor António Augusto Lopes Vaz
Doutor António Carlos de Freitas Ribeiro Saraiva Doutor António Carvalho Almeida Coimbra
Doutor António Fernandes Oliveira Barbosa Ribeiro Braga Doutor António José Pacheco Palha
Doutor António Manuel Sampaio de Araújo Teixeira Doutor Belmiro dos Santos Patrício
Doutor Cândido Alves Hipólito Reis
Doutor Carlos Rodrigo Magalhães Ramalhão Doutor Cassiano Pena de Abreu e Lima Doutor Daniel Filipe de Lima Moura
Doutor Eduardo Jorge Cunha Rodrigues Pereira Doutor Fernando Tavarela Veloso
Doutor Henrique José Ferreira Gonçalves Lecour de Menezes Doutor Jorge Manuel Mergulhão Castro Tavares
Doutor José Carvalho de Oliveira
Doutor José Fernando Barros Castro Correia Doutor José Luís Medina Vieira
Doutor José Manuel Costa Mesquita Guimarães Doutor Levi Eugénio Ribeiro Guerra
Doutor Luís Alberto Martins Gomes de Almeida Doutor Manuel António Caldeira Pais Clemente Doutor Manuel Augusto Cardoso de Oliveira Doutor Manuel Machado Rodrigues Gomes Doutor Manuel Maria Paula Barbosa
Doutora Maria da Conceição Fernandes Marques Magalhães Doutora Maria Isabel Amorim de Azevedo
Doutor Rui Manuel Almeida Mota Cardoso Doutor Serafim Correia Pinto Guimarães
Doutor Valdemar Miguel Botelho dos Santos Cardoso Doutor Walter Friedrich Alfred Osswald
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Ao abrigo do Art.º 8º do Decreto-Lei n.º388/70, fazem parte desta dissertação as seguintes publicações:
I. Pereira S, Fontes F, Sonin T, Dias T, Fragoso M, Castro-Lopes J, Lunet N. Neurological complications of breast cancer: study protocol of a prospective cohort study. BMJ Open 2014; 4(10): e006301
II. Fontes F, Gonçalves M, Maia S, Pereira S, Severo M, Lunet N. Reliability and validity of the Pittsburgh Sleep Quality Index in breast cancer patients. Support Care Cancer 2017 [Epub ahead of print]
III. Fontes F, Pereira S, Castro-Lopes JM, Lunet N. A prospective study on the neurological complications of breast cancer and its treatment: Updated analysis three years after cancer diagnosis. Breast 2016; 29:31-8
IV. Fontes F, Severo M, Gonçalves M, Pereira S, Lunet N. Trajectories of sleep quality during the first three years after cancer diagnosis: a prospective cohort study. Sleep Med 2017; 34:193-199
V. Fontes F, Pereira S, Costa AR, Gonçalves M, Lunet N. The impact of breast cancer treatments on sleep quality 1-year after cancer diagnosis. Support Care Cancer 2017 [Epub ahead of print]
VI. Fontes F, Gonçalves M, Pereira S, Lunet N. Neuropathic pain after breast cancer treatment and its impact on sleep quality one year after cancer diagnosis. Breast 2017; 33:125-131
Em cumprimento com o disposto no referido Decreto-Lei, declaro que participei ativamente na definição dos objetivos de todos os trabalhos que constituem esta tese, bem como na análise dos dados e interpretação dos resultados que estes reportam. Participei na redação da versão inicial do manuscrito I e fui responsável pela redação da versão inicial dos manuscritos II a VI, tendo colaborado ativamente na preparação das versões finais de todos os manuscritos.
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Esta tese foi desenvolvida no Instituto de Saúde Pública da Universidade do Porto, sob orientação do Professor Doutor Nuno Lunet (Faculdade de Medicina e Instituto de Saúde Pública da Universidade do Porto).
Esta investigação foi financiada pelo Fundo Europeu de Desenvolvimento Regional (FEDER) através do Programa Operacional Competitividade e Internacionalização (POCI) (POCI-01-0145-FEDER-016867) e por fundos nacionais através da Fundação para a Ciência e a Tecnologia (FCT), no âmbito do projeto “NEON-BC: Estudo de coorte prospetivo sobre complicações neurológicas do cancro da mama: frequência e impacto em resultados reportados pelos doentes” (Ref.º FCT PTDC/DTP-EPI/7283/20147) e da Unidade de Investigação em Epidemiologia - Instituto de Saúde Pública da Universidade do Porto (EPIUnit) (POCI-01-0145-FEDER-006862; Ref.º FCT UID/DTP/04750/2013). A bolsa de doutoramento SFRH/BD/92630/2013, atribuída a Filipa Fontes, foi cofinanciada pela FCT e pelo Programa Operacional Capital Humano (POCH/FSE).
A gestão da base de dados relativa ao primeiro ano de seguimento da coorte foi financiada pela Cátedra de Medicina da Dor da Faculdade de Medicina da Universidade do Porto e pela Fundação Grünenthal – Portugal.
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OUTORAMENTODoutora Raquel Ângela Silva Soares Lino (Presidente) Faculdade de Medicina da Universidade do Porto
Doutora Marina Pollán Santamaria Instituto de Salud Carlos III
Doutor Luís António Marques Costa
Faculdade de Medicina da Universidade de Lisboa
Doutor Luís Manuel da Cunha Pacheco Figueiredo Escola de Medicina da Universidade do Minho
Doutora Carla Maria de Moura Lopes Faculdade de Medicina da Universidade do Porto
Doutora Ana Azevedo Cardoso de Oliveira Faculdade de Medicina da Universidade do Porto
Doutor Nuno Miguel de Sousa Lunet Faculdade de Medicina da Universidade do Porto
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GRADECIMENTOSAo Professor Nuno Lunet, pela orientação e disponibilidade constantes durante todo este percurso. Agradeço a confiança depositada em mim e a crítica sincera que contribuiu de forma marcante para o meu crescimento pessoal e académico.
À Susana, pela partilha de conhecimento na área da neuro-oncologia e pelo seu papel decisivo no recrutamento e seguimento da coorte de doentes, em cujos dados é baseada esta tese.
À Dra. Marta pela forma entusiasta e generosa com que partilhou comigo o seu conhecimento na área do sono.
A todos os restantes coautores dos artigos que constituem esta tese, pelo seu importante contributo.
À Mariana, pela ajuda na reta final.
À Cláudia e ao Fábio, por estarem presentes mesmos nas ausências, e por me relembrarem o valor da verdadeira amizade.
A todas as colegas do ISPUP, pela forma como me receberam durante estes três anos, e pelos seus contributos para esta tese. Um agradecimento especial à Samantha, pelo esforço acrescido a rever todos os trabalhos.
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ABLE OF CONTENTS AB S T R AC T 3 RE S U M O 9 IN T R O D U C T I O N 1 5 1 . I n c i d e n c e , m o r t a l i t y a n d s u r vi v a l o f b r e a s t c a n c e r 17 2 . Br e a s t c a n c e r t r e a t m e n t 19 2 . 1 . T r e a t m e n t - r e la t e d m o r b id i t y 22 3 . N e u r o p a t h ic p a in f o l lo w i n g b r e a s t c a n c e r t r e a t m e n t 25 3 . 1 . D e f in i t i o n a n d a e t io l o g y 25 3 . 2 . N e u r o p a t h ic p a in a s s e s s m e n t 28 4 . S le e p d is o r d e r s f o ll o w i n g b r e a s t c a n c e r t r e a t m e n t 31 4 . 1 . D e f in i t i o n a n d a e t io l o g y 31 4 . 2 . S le e p m e a s u r e m e n t m e t h o d s 33 AI M S 37 RE S E AR C H ME T H O D S 41 PAP E R S 45 P a p e r I : N e u r o l o g i c a l c o m p l i c a t i o n s o f b r e a s t c a n c e r : s t u d y p r o t o c o l o f a p r o s p e c t i v e c o h o r t s t u d y 47 P a p e r I I : R e l i a b i l i t y a n d v a l i d i t y o f t h e P i t t s b u r g h S l e e p Q u a l i t y I n d e x i n b r e a s t c a n c e r p a t i e n t s 57 P a p e r I I I : A p r o s p e c t i v e s t u d y o n t h e n e u r o l o g i c a l c o m p l i c a t i o n s o f b r e a s t c a n c e r a n d i t s t r e a t m e n t : U p d a t e d a n a l y s i s t h r e e y e a r s a f t e r c a n c e r d i a g n o s i s 67 P a p e r I V : T r a j e c t o r i e s o f s l e e p q u a l i t y d u r i n g t h e f i r s t t h r e e y e a r s a f t e r b r e a s t c a n c e r d i a g n o s i s 77 P a p e r V : T h e i m p a c t o f b r e a s t c a n c e r t r e a t m e n t s o n s l e e p q u a l i t y 1 - y e a r a f t e r c a n c e r d i a g n o s i s 87 P a p e r VI : N e u r o p a t h i c p a i n a f t e r b r e a s t c a n c e r t r e a t m e n t a n d i t s i m p a c t o n s l e e p q u a l i t y o n e y e a r a f t e r c a n c e r d i a g n o s i s 97 GE N E R AL D I S C U S S I O N A N D C O N C L U S I O N S 107 RE F E R E N C E S 1132
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IST OF ABBREVIATIONS AND ACRONYMSALND – Axillary lymph node dissection
EFNS – European Federation of Neurological Societies HER2 – Human epidermal growth factor 2
IASP – International Association for the Study of Pain ICSS – International Cancer Survival Standard IC95% – Intervalos de confiança a 95%
ISI – Insomnia Severity Index YLD – Years lived with disability
NeuPSIG – Neuropathic Pain Special Interest Group OR – Odds ratio
PSQI – Pittsburgh Sleep Quality Index RR – Relative risk
SLNB – Sentinel lymph node biopsy 95%CI – 95% confidence interval
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The increasing number of women surviving for longer periods after the diagnosis of breast cancer emphasizes the importance of evaluating the morbidity resulting from cancer treatments among survivors. Neuropathic pain is a frequent side effect of different breast cancer treatment modalities and may potentially compromise the quality of life of these patients, namely by affecting their sleep quality. Although treatment for breast cancer has been associated with the occurrence of sleep disturbances, data regarding the specific impact of treatment-related neuropathic pain on sleep quality are scarce. Therefore, with this thesis we aimed to contribute to a better understanding of the role of sequelae of breast cancer treatment, namely neuropathic pain, as a mediator of the impact of treatment in the patients’ sleep quality, using a cohort of 506 breast cancer patients followed prospectively for three years since cancer diagnosis. The next paragraphs describe the five specific objectives defined for the thesis, along with the corresponding methods and results:
I. To evaluate the psychometric properties of the Pittsburgh Sleep Quality Index (PSQI) among breast cancer patients;
This objective was accomplished through the analysis of data from patients evaluated three years after cancer diagnosis, among whom the PSQI was used to measure sleep quality. A subsample of 62 participants underwent additional PSQI testing approximately two months later, wore a wrist actigraph for five consecutive days and was reevaluated with the PSQI after one month. A confirmatory factor analysis, considering the components suggested by the principal component analysis, was performed to determine model fit. To evaluate internal consistency and test-retest reliability, Cronbach’s alpha and an intraclass correlation coefficient were calculated, respectively. To assess construct validity, Spearman’s correlation coefficients were computed between PSQI scores, and actigraphy measures and other sleep related constructs.
The principal component analysis suggested one or two components. In the confirmatory analysis, the latter showed better fit to the data, though the two factors were strongly correlated (r=0.76) and internal consistency was not satisfactory for one of the factors. Regarding the one-factor model, both internal consistency (Cronbach’s alpha=0.70) and test-retest reliability (intraclass correlation coefficient=0.76) were adequate. The sleep duration, habitual sleep efficiency and sleep disturbance dimensions of the PSQI were significantly correlated with the corresponding actigraphy
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measures, while the PSQI global score was more strongly correlated with subjective sleep complaints (Spearman’s correlation coefficients ≥0.60).
II. To quantify the frequency of neuropathic pain at one and three years after breast cancer diagnosis;
Data from breast cancer patients who underwent a neurological evaluation before treatment and at one and three years after diagnosis were used in this analysis. The prevalence of neurological complications of breast cancer and its treatment, including neuropathic pain, were recorded at one and three years, and prevalence estimates and the corresponding 95% confidence intervals (95%CI) for each neurological complication were computed.
More than half of the patients (54.7%, 95%CI: 50.2% to 59.2%) presented at least one treatment-related neurological complication, at one and three years after cancer diagnosis. Neuropathic pain was the most frequent in both moments, and there was a slight increase in its prevalence between the first and the third year of follow-up (from 21.1% to 23.6%). Nearly half of those with neuropathic pain at three years were not prevalent cases at the one-year follow-up evaluation.
III. To describe the patterns of variation in different dimensions of sleep quality up to three years after cancer diagnosis;
Data from breast cancer patients followed during three years after cancer diagnosis were used to accomplish this objective. Sleep quality was assessed using the PSQI, at baseline, and one year and three years after enrolment. Model-based clustering was used to identify groups of patients with homogeneous variation in sleep quality.
Three trajectories of variation in sleep quality were identified, named “low”, “medium” and “high”; these included 141, 244 and 73 patients, respectively. Women in the “high” trajectory presented good sleep quality during the three years. The “low” and “medium” trajectories were characterized by poor sleep quality during the whole period; although during the first year, the latter depicted a significant deterioration in sleep quality, namely regarding a decrease in habitual sleep efficiency and an increase in the use of sleep medication, while the former showed a significant improvement. Patients in the “low” trajectory presented a decrease in sleep latency and daytime dysfunction, and
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an increase in sleep duration and habitual sleep efficiency during the first year of follow-up.
IV. To quantify the impact of cancer treatment in patients’ sleep quality one year after cancer diagnosis;
This was accomplished using data from breast cancer patients followed during one year after diagnosis. Sleep quality was evaluated with the PSQI, at baseline and at the one-year follow-up evaluation. Adjusted odds ratios (ORs) were computed to quantify the association between patient characteristics and poor sleep quality (PSQI score>5) at baseline, and relative risks (RRs) were computed for the association between cancer treatments and the occurrence of poor sleep quality at one-year.
A total of 60.2% of the patients had poor sleep quality before breast cancer treatment, especially those with anxiety (OR=2.86, 95%CI: 1.92 to 4.27) or depression (OR=5.25, 95%CI: 2.01 to 13.67). Radiotherapy increased the risk of poor sleep quality at one-year (RR=3.71, 95%CI: 1.15 to 11.96, for a cumulative dose>50grays) and there was a tendency for a higher risk in those submitted to chemotherapy and mastectomy, although not statistically significant.
V. To quantify the impact of neuropathic pain in patients’ sleep quality one year after cancer diagnosis.
Data from patients followed during one year after cancer diagnosis were used for this analysis. Sleep quality was evaluated using the PSQI at baseline and at the one-year follow-up evaluation. Incident neuropathic pain was identified through systematic evaluations performed after surgery, after chemotherapy (when applicable) and one year after enrolment, or through referral by any member of the clinical team. Neuropathic pain severity was quantified using the Brief Pain Inventory severity subscale. Adjusted regression coefficients (β) and 95%CI were used to quantify the relation between neuropathic pain and the variation in the PSQI z-scores.
Neuropathic pain occurrence was associated with a deterioration in sleep quality during the first year of follow-up; this was more pronounced among those with good sleep quality (PSQI≤5) than those with poor sleep quality at baseline (PSQI>5) (β=0.44, 95%CI: 0.11 to 0.77 versus β=0.33, 95%CI: 0.08 to 0.59, respectively). These
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differences were accentuated when only neuropathic pain cases with greater severity were considered (β=0.86, 95%CI: 0.37 to 1.35 versus β=0.31, 95%CI: -0.08 to 0.64, respectively).
The main conclusions of this thesis are the following:
• The unidimensional construct of the PSQI showed adequate reliability and validity, and its global score was more strongly correlated with subjective than objective measures of sleep.
• Neuropathic pain was the most frequent neurological complication of breast cancer treatment, affecting one out of five patients at both one and three years after cancer diagnosis.
• Three trajectories of variation in sleep quality during the first three years after cancer diagnosis were identified. Two trajectories were characterized by poor sleep quality during the whole period, but one depicted a significant deterioration and the other a significant improvement in sleep quality during the first year. The third trajectory was characterized by good sleep quality during the entire follow-up period.
• Nearly two thirds of breast cancer patients presented poor sleep quality prior to the beginning of treatments. Radiotherapy was associated with a higher risk of poor sleep quality one year after cancer diagnosis.
• Neuropathic pain was associated with a deterioration in sleep quality during the first year after cancer diagnosis, especially for more severe pain and among patients with good sleep quality prior to the beginning of breast cancer treatment.
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O aumento do número de mulheres com cancro da mama que vivem por períodos mais longos após o diagnóstico contribui para uma cada vez maior importância da avaliação da morbilidade que resulta dos tratamentos para o cancro. A dor neuropática é um efeito secundário frequente de diferentes tipos de tratamentos, com potencial para comprometer a qualidade de vida das doentes, nomeadamente por poder afetar a qualidade do sono. Apesar de ter sido demonstrado que os tratamentos para o cancro da mama estão associados à ocorrência de distúrbios do sono, pouco se conhece sobre o papel específico desempenhado pela dor neuropática, secundária a esses tratamentos, na qualidade do sono.
Com esta tese pretendemos contribuir para um melhor conhecimento acerca do papel desempenhado pelas sequelas do tratamento do cancro da mama, especificamente a dor neuropática, como mediadoras do impacto dos tratamentos na qualidade de sono das doentes, usando uma coorte 506 doentes com cancro da mama seguidas prospectivamente durante três anos após o diagnóstico. Os parágrafos seguintes descrevem os cinco objetivos específicos definidos para esta tese, bem como os correspondentes métodos e resultados.
I. Avaliar as características psicométricas do Índice da Qualidade de Sono de Pittsburgh (Pittsburgh Sleep Quality Index − PSQI) em doentes com cancro da mama;
Este objetivo foi atingido através da análise dos dados das doentes avaliadas três anos após o diagnóstico, a quem o PSQI foi aplicado para avaliar a qualidade de sono. Adicionalmente, uma sub-amostra de 62 doentes preencheu o PSQI cerca de dois meses mais tarde, usou um actígrafo no pulso durante cinco dias consecutivos e foi reavaliada com o PSQI após um mês. Foi utilizada análise fatorial confirmatória para avaliar o ajuste do modelo previamente sugerido pela análise de componentes principais. A consistência interna foi avaliada pelo alfa de Cronbach e a fiabilidade (teste-reteste) pelo coeficiente de correlação intraclasse. A validade de construto foi avaliada pelo cálculo dos coeficientes de correlação de Spearman entre as classificações obtidas no PSQI, e as medidas obtidas através da actigrafia e outras medidas teoricamente relacionados com a qualidade do sono.
A análise de componentes principais sugeriu um ou dois componentes. Na análise fatorial confirmatória, a solução de dois componentes apresentou um melhor ajuste ao modelo, mas os dois fatores estavam muito correlacionas entre si (r=0.76) e a
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consistência interna não foi satisfatória para um dos dois fatores. Para a solução de um componente, a consistência interna (alfa de Cronbach=0.70) e a fiabilidade foram adequadas (coeficiente de correlação intraclasse=0.76). As dimensões específicas do PSQI “duração do sono”, “eficiência do sono” e “distúrbios do sono” correlacionaram-se significativamente com as medidas correspondentes provenientes da actigrafia; o score global do PSQI corelacionou-se mais fortemente com as queixas subjetivas de sono (r≥0.60).
II. Quantificar a frequência de dor neuropática um e três anos após o diagnóstico de cancro da mama;
Esta análise baseou-se em dados provenientes das doentes avaliadas antes dos tratamentos, e um e três anos após o diagnóstico. A presença de complicações neurológicas, incluindo a dor neuropática, foi registada um e três anos após o diagnóstico, e foram calculadas as respetivas estimativas de prevalência e intervalos de confiança a 95% (IC95%).
Um e três anos após o diagnóstico de cancro da mama, mais de metade das doentes (54.7%, IC95%: 50.2% a 59.2%) apresentaram pelo menos uma complicação neurológica relacionada com os tratamentos. A dor neuropática foi a complicação mais frequente em ambos os momentos, com um ligeiro aumento na sua prevalência entre o primeiro e o terceiro ano de seguimento (de 21.1% para 23.6%). Aproximadamente metade das doentes com dor neuropática aos três anos não apresentavam esta complicação um ano após o diagnóstico.
III. Descrever os padrões de variação de diferentes dimensões da qualidade de sono até três anos após o diagnóstico de cancro;
Este objetivo foi atingido através da análise dos dados das doentes seguidas até três anos após o diagnóstico. A qualidade de sono foi avaliada antes dos tratamentos, e um e três anos após a inclusão das doentes na coorte, através do PSQI. Foram identificados grupos de doentes com variações homogéneas na qualidade de sono através de model-based clustering.
Foram identificadas três trajetórias principais, designadas de “má”, “média” e “boa qualidade de sono” que incluíram respetivamente 141, 244 e 73 doentes. As doentes incluídas na trajetória “boa qualidade de sono” apresentaram boa qualidade de
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sono durante os três anos de seguimento. As trajetórias “má” e “média qualidade de sono” caracterizaram-se por má qualidade de sono durante todo o período em análise. Contudo, as doentes incluídas na trajetória “média qualidade de sono” apresentaram uma deterioração significativa da qualidade de sono durante o primeiro ano, nomeadamente no sentido de uma menor eficiência do sono e maior uso de medicação para o sono, e as doentes na trajetória “má qualidade de sono” apresentaram uma melhoria significativa, particularmente pela diminuição da latência do sono e disfunção diurna e pelo aumento da duração e eficiência do sono.
IV. Quantificar o impacto dos tratamentos para o cancro da mama na qualidade de sono das doentes um ano após o diagnóstico;
Esta análise compreendeu dados provenientes das doentes seguidas durante um ano após o diagnóstico. A qualidade de sono foi avaliada antes dos tratamentos e um ano após a inclusão das doentes na coorte utilizando o PSQI. Foram calculados odds ratios (ORs) ajustados, para quantificar a associação entre características das doentes e a presença de má qualidade de sono antes dos tratamentos (PSQI>5) e riscos relativos (RRs) para a associação entre os tratamentos para o cancro da mama e a incidência de má qualidade de sono um ano após o diagnóstico.
Um total de 60.2% das doentes apresentavam má qualidade de sono antes dos tratamentos para o cancro da mama, especialmente as doentes com ansiedade (OR=2.86, IC95%: 1.92 a 4.27) e depressão (OR=5.25, IC95%: 2.01 a 13.67). A radioterapia associou-se a um maior risco de má qualidade de sono um ano após o diagnóstico (RR=3.71, IC95%: 1.15 a 11.96, doses cumulativas>50grays) e, apesar da ausência de significância estatística, observou-se uma tendência para um maior risco nas doentes submetidas a quimioterapia e mastectomia.
V. Quantificar o impacto da dor neuropática na qualidade de sono das doentes um ano após o diagnóstico.
Este objetivo foi atingido através da análise dos dados das doentes seguidas durante um ano após o diagnóstico. A qualidade de sono foi avaliada antes dos tratamentos e um ano após a inclusão das doentes na coorte, recorrendo ao PSQI. Os casos incidentes de dor neuropática foram identificados através das avaliações sistemáticas efetuadas após a cirurgia, quimioterapia (quando aplicável) e um ano após
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a inclusão na coorte, bem como por referência de qualquer um dos membros da equipa clinica. A severidade da dor foi quantificada através do Inventário Resumido da Dor (Brief Pain Inventory). Foram calculados coeficientes de regressão (β) ajustados, para quantificar a relação entre a dor neuropática e a variação do valor padronizado de PSQI (z-scores) durante o primeiro ano após o diagnóstico.
A ocorrência de dor neuropática associou-se a uma deterioração da qualidade do sono durante o primeiro ano após o diagnóstico, mais acentuada nas doentes com boa (PSQI≤5) do que com má qualidade de sono (PSQI>5) antes de iniciar tratamentos (β=0.44, IC95%: 0.11 a 0.77 versus β=0.33, IC95%: 0.08 a 0.59, respetivamente). Estas diferenças acentuaram-se quando foram analisados apenas os casos de dor com maior severidade (β=0.86, IC95%: 0.37 a 1.35 versus β=0.31, IC95%: -0.08 a 0.64, respetivamente).
As principais conclusões desta tese foram as seguintes:
• A solução unidimensional do PSQI demonstrou consistência e validade adequadas, e o seu valor global correlacionou-se mais fortemente com medidas subjetivas do com medidas objetivas da qualidade do sono.
• Um e três anos após o diagnóstico de cancro da mama, a dor neuropática foi a complicação neurológica mais frequente, afetando aproximadamente uma em cada cinco doentes.
• Foram identificadas três trajetórias de variação na qualidade do sono durante os três primeiros anos após o diagnóstico de cancro. Duas das trajetórias caracterizaram-se por má qualidade de sono durante todo o período, mas uma apresentou uma deterioração e a outra uma melhoria significativa na qualidade do sono durante o primeiro ano de seguimento. A terceira trajetória caracterizou-se por boa qualidade de sono durante todo o período em análise. • Cerca de dois terços das doentes apresentavam má qualidade do sono mesmo antes de iniciarem tratamentos para o cancro da mama. A radioterapia associou-se a um maior risco de má qualidade do sono um ano após o diagnóstico.
• A dor neuropática associou-se a deterioração da qualidade do sono durante o primeiro ano após o diagnóstico, principalmente nas doentes com dor com maior severidade e com boa qualidade do sono antes de iniciar tratamentos.
15
17
1. I
N C I D E N C E,
M O R T AL I T Y AN D S U R V I V AL O F B R E AS T C AN C E RAmong women, breast cancer is the most frequent cancer, both in developed and developing countries, estimated to be responsible for 25.1% of all cancer cases diagnosed in 2012.1 It is the leading cause of oncological death worldwide (14.7% of the
total number of cancer deaths), and in more developed regions it is now the second cause of cancer death, after lung cancer.1 In Portugal, breast cancer was estimated to
account for approximately six thousand new cases and 1570 deaths in 2012, which correspond to 29.4% of all cancer cases and 16.0% of all cancer deaths among women, respectively.1
Figure 1 depicts the estimated age-standardized incidence (Figure 1A) and mortality (Figure 1B) rates in 2012, by region. The highest figures for incidence are observed in Northern America, Western and Northern Europe, and Oceania (>85.0 per 100 000 women); whereas for mortality the highest are in Western and Northern Africa, Central and Eastern Europe, and Northern Europe (>16.0 per 100 000 women).
During the last decades, an upward trend in breast cancer incidence rates has been observed, largely in more developed settings.2,3 In addition to the greater exposure
to factors that increase the risk of breast cancer (e.g., delayed childbearing, lower parity, use of hormone-replacement therapy, obesity and physical inactivity), the widespread use of mammographic screening has also contributed to these trends.4,5 Since the
beginning of the millennium, a downward trend in incidence started to be observed in some high income Western nations, including the United States of America,6,7 the United
Kingdom,8 France9 and Australia.10 The decrease in the use of hormone-replacement
therapy, which is more frequent in these settings than in the rest of the world, has been presented as the principal explanation for this pattern of variation.11
As a result of the increase in the proportion of cancers detected at earlier stages of the disease and the more frequent use of more effective treatment, a substantial reduction in breast cancer mortality has been observed during the last decades in most more developed countries.12-14 On the contrary, mortality has increased in many African
and Asian countries, reflecting changes in reproductive factors and lifestyles, as well as lack of screening programmes.14,15
18
FIGURE 1. Estimated age-standardized (World Standard Population) incidence rates (A) and mortality rates (B), per 100 000 women (Source: GLOBOCAN 2012 [International Agency for Research on Cancer]1)
According to the data available from the CONCORD-2 study, the average 5-year age-standardized (International Cancer Survival Standard [ICSS]) net survival for women diagnosed in 2005-2009 and followed up to December 2009 was 85% or higher in 17 countries around the world16 but was lower than 60% in Mongolia (57%) and South
Africa (53%).16
The European mean 5-year age-standardized (ICSS) relative survival for breast cancer increased from 73.5%, in women diagnosed during 1987-1989,17 to 81.8%, in
those diagnosed during 2000-2007.18 However, there was a high variability observed
across countries, with 5-year age-standardized relative survival ranging from 66.7% in Lithuania to 87.2% in Iceland; in Portugal, it was above the average at 83.3%.18
A
19
2. B
R E AS T C AN C E R T R E AT M E N TBreast cancer treatment has changed considerably during the past decades.19 In
the 1960s, when the first mammographic evaluations started to arise, allowing the detection of nonpalpable tumours, radical mastectomy was the standard treatment.19 At
present, breast cancer management often requires a combination of therapies which includes surgery, radiation therapy, chemotherapy, endocrine therapy and targeted therapy.
Surgery
Since the 1980s, a trend towards an increasing use of breast-conservative treatment has been observed, supported by randomised clinical trials reporting similar survival rates, over long follow-up periods, for women treated by mastectomy or breast-conservative surgery.20-22 However, in some patients, mastectomy is still performed due
to large tumour size (relative to breast size), tumour multicentricity, inability to achieve negative surgical margins after multiple surgical resections, history of radiation to the chest wall and/or breast, contraindications for radiotherapy or even patient option.23
For patients proposed to mastectomy, the possibility of immediate or delayed breast reconstruction should be discussed.24 Published evidence indicates that breast
reconstruction does not interfere with further treatment for advanced cancer25 and there
are no significant differences in the survival rates between patients undergoing immediate or delayed reconstruction.25-28 Also, there is no evidence that reconstruction
makes detection of local recurrence more difficult or that patients should wait one or two years after mastectomy before being offered reconstruction.29
In women with inoperable locally advanced breast cancer, systemic therapy should be the initial treatment. If the cancer remains inoperable after systemic therapy (alone or with radiation therapy), a “palliative” mastectomy is not recommended, unless surgery is likely to result in an overall improvement in quality of life.30
Regional lymph node status at the moment of cancer diagnosis is considered one of the strongest predictors of long-term prognosis in breast cancer patients.29 Sentinel
lymph node biopsy (SLNB), rather than axillary lymph node dissection (ALND), is now accepted as the standard of care for axillary node staging in early, clinically node-negative breast cancer, unless axillary node involvement is proven through
ultrasound-20
guided biopsy.31 SLNB was shown to yield a small proportion of false negatives and to
be associated with a significant reduction in arm and shoulder morbidity, especially lymphoedema, and better quality of life, when compared to ALND.32 When the sentinel
lymph node is positive, further axillary treatment (ALND and/or radiotherapy), as well as adjuvant systemic therapy, is recommended.23
Radiation therapy
Adjuvant radiotherapy to the breast or chest wall, as applicable, has been strongly recommended in patients who have undergone breast-conserving surgery33 and
in those submitted to mastectomy who are node-positive (≥4 lymph nodes involved).34
Among the latter, radiotherapy reduces the 10-year risk of locoregional and distant recurrence by 10% and the 20-year risk of breast cancer-related mortality by 8%.34 In the
former, radiotherapy reduces the 10-year risk of any recurrence by 15% and the 15-year risk of breast cancer-related mortality by 4%.33 Since the benefits of radiotherapy
following mastectomy seem to be independent from the number of axillary lymph nodes involved and from the administration of adjuvant systemic treatments,34 recent guidelines
also recommend the use of post-mastectomy radiotherapy in patients with one to three positive axillary lymph nodes.29,35,36
In addition to radiotherapy to the breast, recent results support comprehensive locoregional radiotherapy including the chest wall and all regional lymph nodes.37,38
Chemotherapy
Despite improvements in treatment strategies and the availability of drugs used in chemotherapy, the specific groups of patients that benefit from chemotherapy are not well defined and biomarkers for response are lacking.39 The TAILORx and the MINDACT
trials were carried out to provide clinical evidence of the benefits of adding biomarkers to the standard criteria to select patients for chemotherapy.40,41 However, at the moment,
gene expression profiling tests are not routinely available in clinical practice. Nevertheless, an overview of clinical trials on the benefits of chemotherapy showed that women under 50 years of age treated with chemotherapy gained an average of 10.3 months relapse-free survival and 5.4 months of overall survival within 10 years compared with those not receiving chemotherapy; for older women, average gains were 6.8 months and 2.9 months, respectively.42
The most recent publication of The Early Breast Cancer Trialists’ Collaborative Group stated that the relative benefit of chemotherapy is similar in all subgroups
21
independent of age, nodal status, tumour diameter or differentiation, oestrogen receptor status or tamoxifen use.43 Notwithstanding this review, both the St. Gallen and the
European Society for Medical Oncology Clinical Practice Guidelines consider that indications for adjuvant systemic treatment should include high histologic grade breast cancer, high values of Ki-67, low hormone receptor status, overexpression of human epidermal growth factor 2 (HER2) and “triple negative” breast cancer.29,44
Anthracyclines (e.g., doxorubicin and epirubicin) and taxanes (e.g., docetaxel and paclitaxel) are among the most commonly used drugs included in chemotherapeutic schemes for breast cancer patients.29,44 The addition of taxanes has been demonstrated
to improve chemotherapy efficacy, even though there is an increase in the non-cardiac toxicity.43,45 When included in the same regimen, the sequential use of anthracyclines
and taxanes has been associated with a significant reduction in both disease-free and overall survival, when compared to the concomitant used of the two drugs.46
Endocrine therapy
Endocrine therapy is indicated in all patients with detectable oestrogen receptor expression, independently of the use of chemotherapy and/or targeted therapy.47,48 The
choice of agent used is mainly determined by the menopausal status of women.
Tamoxifen, with or without ovarian suppression, is recommended for premenopausal women.29,44 The ATLAS study demonstrated an advantage of
performing tamoxifen during 10 years rather than stopping at five.49 In addition, it was
demonstrated that a switch to letrozole is beneficial in patients becoming postmenopausal during the first five years of tamoxifen use.50 Recently, the SOFT study
demonstrated the benefit of adding ovarian function suppression to tamoxifen in women who are at sufficient risk to warrant adjuvant chemotherapy and remain premenopausal afterward.51 Results from the SOFT and TEXT trials showed even greater benefit when
ovarian suppression was added to the aromatase inhibitor exemestane.52
Aromatase inhibitors are the preferred option for postmenopausal women. They can be used as primary (initial endocrine therapy), sequential (after two or three years of tamoxifen) or extended (after five years of tamoxifen) therapy.53 The extension of
treatment with adjuvant aromatase inhibitor for 10 years rather than the previously recommended five years, after any duration of prior treatment with tamoxifen, resulted in a significantly lower risk of disease recurrence and contralateral incidence of breast cancer in the MA.17R trial.54
22
Targeted therapy
Approximately 15% to 20% of primary breast cancer patients have overexpression and/or amplification of HER2 on the surface of tumour cells.55
Trastuzumab, a recombinant monoclonal antibody, was the first agent developed to target the HER2 pathway, and its use in association with chemotherapy results in a 10% overall improvement in long-term disease free-survival and a 9% increase in 10-year overall survival, when compared with chemotherapy alone.56-58
The European Society of Breast Cancer Specialists recommends treatment with adjuvant trastuzumab for one year, together with or after chemotherapy, in HER2-positive patients, with either node-HER2-positive or high-risk node-negative breast cancer (tumour size > 1 cm), having a left ventricular ejection fraction of at least 55% and without important cardiovascular risk factors, regardless of age.59 The HERA trial60 showed no
additional benefit of using trastuzumab during two years, and the PHARE trial 61 failed to
show that six months of treatment of trastuzumab was non-inferior to 12 months of treatment.
Since a meaningful proportion of patients with HER2-positive breast cancer develop either primary or secondary resistance to trastuzumab, several new anti-HER2 agents are currently being developed.62 Recently, the use of pertumuzab with
trastuzumab and docetaxel was approved in the neoadjuvant setting, since its addition has been demonstrated to improve both progression-free and overall survival.63
2.1. TR E A T M E N T-R E L AT E D M O R B I D I T Y
The decrease of breast cancer mortality in many developed countries,12,13 along
with the increase of relative survival,16,18 strengthen the importance of morbidity due to
side effects from treatments as one of the components of the global burden of breast cancer. The quantification of the burden of non-fatal health outcomes was one of the main goals of the Global Burden of Disease study, when it was launched in the 1990s.64
This study introduced the disability-adjusted life-year as a measure of overall disease burden that, in addition to capture the years of life lost due to premature mortality, also includes the years of life lived in less than ideal health (years lived with disability [YLD]). According to the Global Burden of Disease study 2015, the age-standardized (World Standard Population) rate of disability-adjusted life-years due to breast cancer decreased from 231.4 per 100 000 women in 2005 to 217.1 per 100 000 women in 2015.65 However, the breast cancer age-standardized rates of YLD increased from 30.5
23
per 100 000 women to 36.1 per 100 000 women in the same period. In 2015, breast cancer was the leading cause of YLD due to cancer,66 which highlights the importance
of the evaluation of morbidity related with breast cancer treatments among survivors. Impairments of the upper extremity function, lymphoedema, fatigue, poor sleep quality, decreased sexual functioning, loss of fertility, chronic pain, anxiety and depression are among the most frequent late and long-term effects of breast cancer treatment.67 Limitations of the upper extremity function following surgery and the
occurrence of lymphoedema secondary to both surgery and radiotherapy, decrease the ability to perform activities of daily living, impact employment, and bring body image concerns and social stigma.68-70 Fatigue is a frequent side effect of both radiotherapy and
chemotherapy that may persist for many years after treatment and interfere with patients’ basic daily activities.71 Sleep disturbances are frequently associated with adjuvant
treatments for breast cancer72 and have been demonstrated to be an important
contributor to poor quality of life.73,74 Premature ovarian failure and sexual complains,
that frequently occur as side effects of chemotherapy, have a negative impact in women’s reproductive and sexual life.75,76 Treatment-related neuropathic pain, the major
contributor to chronic pain among breast cancer patients,77 has been demonstrated to
be associated with high impairment of physical, psychological and social dimensions of health,78 and may persist for decades after treatment.79 Anxiety has been described to
be frequent among women performing surgery, radiotherapy or chemotherapy and tends to persist beyond the acute stage of treatment.80 Similarly, breast cancer patients have
a higher risk of long-term symptoms of depression when compared to the general female population81 and may also experience difficulties in coping with pain and disability caused
by breast cancer treatment.82
Previous studies reported employment challenges due to cancer-related side effects among breast cancer survivors, mainly in those submitted to more aggressive therapy.83,84 Furthermore, the financial strain of treatment, from loss of productivity to
medical costs, remain after the end of cancer treatment, which often leads to dependence on family members and economic concerns that could affect social relationships.85
There is increasing recognition that breast cancer patients often experience concurrent groups of symptoms, usually referred as “symptom clusters”, and defined as “two or more symptoms that are related to each other and that occur together”.86 Among
the above reported treatment-related side effects, chronic pain and insomnia are often reported as being part of a symptom cluster that frequently also includes fatigue, anxiety and depression.87-89 In the last few decades, although there was a consistent increase in
24
the number of publications on these topics (Figure 2), those including the words “insomnia” or “sleep” and those with the expression “chronic pain”, accounted for only approximately half and one quarter, respectively, of the number of those including “anxiety”, “depression” or “fatigue”. In addition, when considering “neuropathic pain”,90
the disparity in the number of articles was even higher. This highlights that although neuropathic pain and sleep disturbances are frequent and considered important sources of disability among those treated for breast cancer,73,74,78 there is dearth of studies
addressing more specifically these issues among breast cancer patients.
FIGURE 2. Number of articles published per year, between 1990 and 2016, according to different search expressionsa
25
3. N
E U R O P AT H I C P AI N F O L L O W I N G B R E AS T C A N C E R T R E AT M E N TNeuropathic pain is a frequent complication of both surgical and adjuvant treatments for breast cancer,91,92 estimated to affect almost a third of breast cancer
patients during the first year after cancer diagnosis.93
3.1. DE F I N I T I O N A N D A E T I O L O G Y
The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”,94 traditionally classified as being
nociceptive or neuropathic. In 1994, IASP defined neuropathic pain for the first time as “pain initiated or caused by a primary lesion or dysfunction in the nervous system”,94and recently redefined it as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system”.95 The elimination of “dysfunction” from the original
definition and the introduction of the requirement of a specific lesion of the somatosensory system allowed, on the one hand, the distinction between neuropathic pain and pain such as that caused by neuroplastic changes in response to strong nociceptive system (e.g., inflammatory pain) and, on the other hand, the differentiation of neuropathic pain from pain caused by lesions in other parts of the nervous system (e.g., pain associated with muscular spasticity associated with lesions of central motor pathways).95
It has long been recognized that neuropathic pain is not a single disease but represents a syndrome, which can be characterized by a collection of specific signs and symptoms with multiple underlying pathophysiological mechanisms, which are unstable over time.96 Due to this and the fact that among cancer patients multiple pain aetiologies
may coexist,97 cancer pain is often classified as mixed rather than as exclusively
neuropathic or nociceptive. Therefore, it has been argued that the question should not be “does the patient have neuropathic pain or not” but rather “is this pain of predominantly neuropathy origin?”96 It has been described that about 40% of cancer patients are
affected by pain that is predominantly neuropathic in character.90
Among breast cancer patients, neuropathic pain may occur due to: (a) cancer, when resulting from the compression or infiltration of the central or peripheral nervous system;98 (b) comorbid conditions, either as a consequence of diseases related to cancer
26
(e.g., post-herpetic neuralgia) or other diseases not related to cancer (e.g., painful diabetic neuropathy); and (c) cancer treatment, as a consequence of intraoperative damage to nervous system structures91 or following radiotherapy and chemotherapy.92
A systematic review on the mechanisms involved in neuropathic pain occurrence, concluded that nearly two thirds of the cases of neuropathic pain in cancer patients were caused directly by cancer, while cancer treatment, such as surgery or chemotherapy, account for just over one fifth of the cases, and comorbid diseases were responsible for an additional 10-15%.90 This aetiological profile described for neuropathic pain in cancer
patients differs from the reported for cancer pain in general. A prospective study including more than 2200 cancer patients showed that the causes of pain were related to cancer, treatment and comorbidities in 75.7%, 11.4% and 10.8% of the cases, respectively.99
Although these studies not specifically addressing patients with breast cancer and likely not reflecting the current state of the art of cancer treatment, the results suggests that neuropathic pain in cancer patients may be caused by cancer treatment more often than pain in general.
Neuropathic pain following breast cancer treatment can arise as a consequence of breast cancer surgery, radiotherapy or chemotherapy.91,92 There is no evidence that
hormonal agents, such as tamoxifen and aromatase inhibitors, and trastuzumab cause neuropathy.100 A recent study addressing the incidence of neurological complications
among breast cancer patients concluded that almost one third were diagnosed with treatment-related neuropathic pain during the first year after cancer diagnosis.93
Surgery-related neuropathic pain
Damage of peripheral nerves can occur during surgical interventions, such as breast-conserving surgery, mastectomy, breast reconstruction and ALND, which may result in neuropathic pain typically localized in the axilla, medial upper arm, and/or the anterior chest wall of the affected side.101 In addition to damage of the intercostobrachial
nerve occurring with ALND, which has been considered the most common cause of surgery-related neuropathic pain,91 it can also be damaged in approximately 5% of the
patients undergoing SLNB.102 Regardless of the type of breast surgery, postsurgical
neuromas are also a cause of neuropathic pain among women undergoing surgical treatment for breast cancer.91 Phantom breast pain, defined as the painful sensation that
the removed breast is still present among those submitted to mastectomy, is considered another less studied neuropathic pain condition.91
27
Radiation-induced neuropathic pain
Neuropathic pain is an established side effect of radiation therapy for breast cancer.92 The mechanism of radiation-induced plexopathy is believed to be related with
fibrosis of connective tissues around peripheral nerves, damage of capillary blood vessels resulting in ischemia, and demyelination of axons.103,104 The brachial plexus is
particularly susceptible to radiation injury when the supraclavicular fossa is irradiated, which is recommended in patients with positive axillary lymph nodes.36 The total dose of
radiation, dose per fraction, treatment duration, volume of tissue irradiated and concomitant chemotherapy, are among the documented risk factors for radiation-induced plexopathy.103,104
Radiation effects can include early plexopathy, usually mild and transient, as well as delayed plexopathy, occurring months to decades after radiation therapy, which has been described as more common and often progressive.79
Chemotherapy-induced neuropathic pain
Chemotherapy-induced peripheral neuropathy is one of the most frequent adverse effects of many commonly used chemotherapeutic agents.105,106 It may interfere
with the treatment effects, due to dose reductions, treatments delays or even premature cessation of chemotherapy. Symptoms are predominantly sensory, often affecting both hands and feet, with a predominantly “glove and stocking” distribution characterized by sensory loss, paraesthesia, numbness, and tingling, that may be aggravated by pain.107,108 Overall, motor and autonomic symptoms, occurring more frequently with vinca
alkaloids than with other classes of chemotherapeutic agents, are less frequent than sensory symptoms.104,106
The general clinical presentation of chemotherapy-induced peripheral neuropathy is similar across different chemotherapeutic options. However, distinct components of the nervous system, from the sensory cell bodies across the dorsal root ganglion to the distal nerve terminals, are affected by different drugs and different underlying mechanisms have been proposed for different drugs; yet, its pathophysiology remains poorly understood.105,106
28
3.2. NE U R O P A T H I C P A I N A S S E S S M E N T
In 2008, a grading system to classify the certainly with which the presence or absence of neuropathic pain can be determined was proposed by Treede et al.95 and
later adopted by the European Federation of Neurological Societies (EFNS) and the Neuropathic Pain Special Interest Group (NeuPSIG) of the IASP in their guidelines on neuropathic pain assessment.109,110 This contributed to overcome the absence of a
specific diagnostic tool allowing for an unequivocal diagnosis of neuropathic pain. The neuropathic pain grading system consists of four criteria: 1) pain with a distinct neuroanatomically plausible distribution; 2) a history of a relevant lesion or disease affecting the somatosensory system; 3) confirmatory tests demonstrating presence of negative and positive sensory signs confined to the innervation territory of the injured nervous structure; 4) diagnostic tests confirming a lesion or disease entity underlying the neuropathic pain.95 Criteria 1 and 2 must be met to classify neuropathic
pain as “possible”. The clinical examination of a patient with “possible neuropathic pain” is necessary to confirm or reject the hypothesis of a lesion or disease of the somatosensory system, derived from clinical history. Therefore, when one of criterion 3 or criterion 4 are met, neuropathic pain is classified as “probable”, and when both criteria 3 and 4 are satisfied, neuropathic pain is classified as “definite” (Figure 3).95 The levels
“definite” and “probable” indicate that the presence of this condition has been established.95
29
In recent years, several screening tools based on self-reported pain description, with or without clinical examination, have been developed and validated to identify pain of predominantly neuropathic origin.111-115 Although there are some differences in the
structure of these instruments, a few symptoms are considered by all of them to describe pain (Table 1). Clinical examination of sensory signs is only used by two of the tools (Douleur Neuropathique en 4 questions and Leeds Assessment of Neuropathic Symptoms and Signs).111,113 In the absence of a formally recognized “gold standard”,
clinical examination of patients has been used to evaluate the sensitivity and specificity of these instruments, yielding values ranging from 66% to 91% and from 74% to 94%, respectively.116
TABLE 1. Comparison of items evaluated in five neuropathic screening tools (Adapted from Bennet et
al.116)
DN4113 ID Pain115 LANSS111 NPQ114 painDETECT112
Symptoms
Pricking, tingling, pins and needles ✓ ✓ ✓ ✓ ✓
Electric shocks or shooting ✓ ✓ ✓ ✓ ✓
Hot or burning ✓ ✓ ✓ ✓ ✓
Numbness ✓ ✓ ✓ ✓
Pain evoked by light touching ✓ ✓ ✓ ✓
Painful cold or zing pain ✓ ✓
Pain evoked by mild pressure ✓
Pain evoked by heat or cold ✓
Pain evoked by changes in weather ✓
Pain limited to joints a ✓
Itching ✓
Temporal patterns ✓
Radiation of pain ✓
Autonomic changes ✓
Signs (clinical examination)
Brush allodynia ✓ ✓
Raised soft touch threshold ✓
Raised pin prick threshold ✓ ✓
DN4, Douleur Neuropathique en 4 questions; LANSS, Leeds Assessment of Neuropathic Symptoms and Signs; NPQ, Neuropathic Pain Questionnaire.
a Used to identify non-neuropathic pain.
Previous studies reported that neuropathic pain screening tools presented poor performance when applied in patients with cancer.117,118 The fact that most of them were
validated in patients with non-oncological pain, among whom positive sensory phenomena, such as hyperalgesia and allodynia, are common, has been described as the main cause for this.116 Furthermore, they fail to identify 10% to 20% of patients with
clinically diagnosed neuropathic pain, suggesting that they may offer guidance for further diagnostic procedures but cannot replace careful clinical judgement.109,110 Nevertheless,
30
both the EFNS and NeuPSIG assessment guidelines accept the use of screening tools to identify patients with “possible” neuropathic pain.109,110
31
4. S
L E E P D I S O R D E R S F O L L O W I N G B R E AS T C AN C E R T R E AT M E N TCancer treatments, mostly those involving chemotherapy or radiotherapy, have been associated with higher levels of sleep disturbances among breast cancer patients.72
Although neuropathic pain is a recognized frequent side effect of treatments for breast cancer,91,92 there is scarce data evaluating its impact on sleep quality among these
patients.
4.1. DE F I N I T I O N A N D A E T I O L O G Y
The term sleep disorders has been used to refer to a wide range of symptoms that include insomnia, excessive day sleepiness and/or abnormal movements, behaviours or sensations during sleep.119 Furthermore, different terms, such as
insomnia, impaired sleep, sleep dysfunctions, poor sleep quality and sleep disturbances, have been used interchangeably as synonyms of sleep disorders.120
Based on Spiellman’s three factor model of insomnia,121 aetiologic factors
involved in the development of sleep disturbances among cancer patients have been grouped in three main groups: (a) predisposing factors, that increase the individuals’ general vulnerability to develop sleep disturbances during their lifetime (e.g., being female, older age, personal and familiar history of insomnia and the co-occurrence of anxiety or depression); (b) perpetuating factors, including those contributing to the maintenance of sleep disturbances over time (e.g., maladaptive sleep behaviours and faulty beliefs and attitudes about sleep); and (c) precipitating factors, i.e., situational conditions that trigger the onset of sleep disturbances at a specific point in time (e.g., stressful life events).122
The diagnosis of cancer, as well as its treatment and side effects, have been reported as examples of stressful events that may precipitate the development of sleep disturbances among cancer patients.122 In accordance with this, a recent systematic
review assessing the association between different breast cancer treatments and sleep disturbances, showed that women submitted to chemotherapy or radiotherapy reported higher levels of sleep disturbances than those not submitted to these treatments, and that chemotherapy was also associated with greater levels of sleep disturbances than radiotherapy; less consistent findings were noted regarding the impact of surgical treatments and the effect of endocrine therapy (Figure 4). The lack of prospective studies
32
with an evaluation before the beginning of treatment has been reported as one of the main factors contributing to the absence of more robust findings in this topic, in addition to the evidence of reporting bias and to the fact that most studies did not control for the effect of potential confounders.72
FIGURE 4. Systematic review evaluating the association between breast cancer treatment and sleep disturbances, namely surgical treatments (A), chemotherapy (B), radiotherapy (C) and hormonal therapy (D) (Adapted from Costa et al.72)
AC, Doxorubicin + cyclophosphamide; CTX, Chemotherapy; FEC, 5-Fluorouracil + epirubicin + cyclophosphamide; HT, Hormonal therapy; RT, Radiotherapy.
Although neuropathic pain has been reported as a frequent side effect of breast cancer91,92, and therefore may act as a precipitating factor for the development of sleep
disturbances among these patients, data measuring the impact of treatment-related neuropathic pain in sleep quality are scarce. In a study assessing the relationship between symptom clusters and chemotherapy-induced peripheral neuropathic pain, the authors found that the “high cluster group” included patients who reported both high levels of pain with neuropathic characteristics and sleep disturbances.123 In another
study, it was concluded that the pharmacological treatment of neuropathic pain was associated with an improvement in sleep quality eight weeks later.124
33 4.2. SL E E P M E A S U R E M E N T M E T H O D S
Several well-established methods are available for characterizing different aspects of sleep and sleep-related outcomes. Although the usefulness of each method may vary according to the intended purpose, they should be seen as complementary, since they assess different components of the construct of sleep.125,126
Polysomnography
Polysomnography is considered the “gold standard” of sleep evaluation and can be conducted both in laboratory or ambulatory settings.125,126 It includes several types of
electrophysiological monitoring, including electroencephalography, electrooculography and electromyography, all used to provide the necessary information to distinguish sleep from wake state and to determine the patients’ sleep stages, allowing the identification of several sleep disorders127,128 Additional measures of cardiac, respiratory and
neurological functions are often obtained to evaluate the association of sleep features with cardiovascular events and to diagnose sleep-related breathing disorders and periodic limb movements during sleep.127,128
The main advantage of polysomnography in relation to the other available methods is the ability to measure physiological properties of sleep and to evaluate others physiological and pathophysiological parameters. The intrusive nature of sleep recordings, given the need for attached sensors, and the high cost of the equipment, sensors, and personnel needed to obtain and score the results, precludes its use in studies involving a large number of participants.126 In addition, it is commonly conducted
during a maximum of three nights, raising the possibility that it may not capture the features of sleep that may not be present every night. Finally, when performed in laboratory settings, as the patients are not in their natural sleep environment, they may sleep differently, especially during the first night (“first-night effect”); the discarding of the first night’s data or the realization of polysomnography in ambulatory settings may minimize this handicap.128
Actigraphy
Actigraphy is the measurement of physical movement, obtained with the use of motion sensors, typically in a small device worn on the nondominant wrist, although they can also be placed on the ankle or trunk.129 A recording of at least three consecutive
24-hour periods is recommended, but longer periods provide a more representative assessment of sleep-wake patterns.130 Data derived from actigraphy can be downloaded
