( PDF ) Avaliação dos efeitos colaterais da iodoterapia adjuvante sobre as glândulas salivares em pacientes com carcinoma bem-diferenciado de tireóide

Download PDF

ads:

AVALIAÇÃO DOS EFEITOS COLATERAIS DA

IODOTERAPIA ADJUVANTE SOBRE AS GLÂNDULAS

SALIVARES EM PACIENTES COM CARCINOMA

BEM-DIFERENCIADO DE TIREÓIDE

JULIANA PEREIRA ALMEIDA

Tese de doutorado apresentada à Fundação Antônio

Prudente para a obtenção do título de Doutor em

Ciências

Área de Concentração: Oncologia

Orientador: Prof. Dr. Luiz Paulo Kowalski

Co-Orientador: Dr. Eduardo Nóbrega Pereira Lima

São Paulo

2009

ads:

Livros Grátis

http://www.livrosgratis.com.br

Milhares de livros grátis para download.

FICHA CATALOGRÁFICA

Preparada pela Biblioteca da Fundação Antônio Prudente

Almeida, Juliana Pereira

Avaliação dos efeitos colaterais da iodoterapia adjuvante sobre as

glândulas salivares em pacientes com carcinoma bem-diferenciado de

tireóide / Juliana Pereira Almeida – São Paulo, 2009.

103p.

Tese (Doutorado)-Fundação Antônio Prudente.

Curso de Pós-Graduação em Ciências - Área de concentração: Oncologia.

Orientador: Luiz Paulo Kowalski

Descritores: 1. CÂNCER DE TIREÓIDE. 2. IODO. 3. GLÂNDULAS

SALIVARES/efeitos da radiação. 4. SIALADENITE. 5. XEROSTOMIA. 6.

AMIFOSTINA. 7. QUALIDADE DE VIDA.

ads:

DEDICATÓRIA

Dedico esta tese à minha mãe Mayza, que sempre esteve ao meu lado

incentivando meus sonhos e viabilizando meios para que eu os conquistasse. Mãe

hoje este título não é só meu, mas seu também. Obrigada por tanta dedicação!

AGRADECIMENTOS ESPECIAIS

Agradeço a todos da minha família, mãe, irmãos, tios(as), primos(as), sogro(a),

cunhada, que desde o início da minha jornada sempre estiveram ao meu lado e

tornaram este caminho mais fácil.

Agradeço ao meu futuro esposo Eduardo, que durante todo o período do doutorado

sempre esteve ao meu lado me dando apoio nas horas difícies e comemorando junto

minhas conquistas.

Ao doutor José Magrin, um grande amigo por quem tenho uma imensa consideração,

que desde a residência me ensinou com tanta paciência, que me amparou e

aconselhou nas horas difíceis e acompanhou toda a minha história dentro do Hospital

A. C. Camargo, meu muito obrigada pela sua amizade.

AGRADECIMENTOS

Às pessoas que tornaram possível o desenvolvimento desta tese:

Ao meu orientador Prof. Dr. Luiz Paulo Kowalski que acreditou no meu potencial e

sempre direcionou meus passos nos momentos difíceis.

À Pós-Graduação da Fundação Antônio Prudente por me dar a oportunidade de

crescer e aprimorar meus conhecimentos, tanto com a oportunidade deste doutorado

como a oportunidade de buscar conhecimentos fora do país em Instituições

renomadas.

À toda a equipe do Departamento de Cirurgia de Cabeça e Pescoço do Hospital A. C.

Camargo, médicos, residentes e funcionários, que participaram na captação de

pacientes para o desenvolvimento desta tese.

À toda a equipe do Departamento de Medicina Nuclear do Hospital A.C. Camargo,

médicos, biomédicas e funcionários, que possibilitaram o desenvolvimento da

primeira fase deste estudo.

À toda a equipe do SAME que por inúmeras vezes durante minha estadia no Hospital

A. C. Camargo me atendeu com um sorriso no rosto e prontos para facilitar o

percursso.

Ao Departamento de Medicina Nuclear do Hospital Samaritano, Dra. Marília

Martins Silveira Marone e Guilherme de Carvalho Campos Neto, que foram

importantes para o meu crescimento e conclusões finais deste trabalho.

Ao Hospital de Câncer de Barretos, nas pessoas do Dr. André Lopes Carvalho, Dr.

Euclides Timóteo Rocha, Dr. Marcelo José dos Santos, Dionísio Nepomuceno

Viviani, Renato Barra, Ana Luiza Pereira, Eduardo Tinóis, Stela Verzinhasse e

Milene Foschini pela abertura como me receberam e pelo belo trabalho que

desenvolvemos juntos. Obrigada.

À toda a equipe da Biblioteca do Hospital A. C. Camargo sempre disposta a nos

ajudar e que facilitam tanto nossa vida.

RESUMO

Almeida JP. Avaliação dos efeitos colaterais da iodoterapia adjuvante sobre as

glândulas salivares em pacientes com carcinoma bem-diferenciado de tireóide.

São Paulo; 2009. [Tese de Doutorado-Fundação Antônio Prudente].

Introdução: A saliva exerce funções fundamentais para a manutenção da função

oral. Alterações qualitativas ou quantitativas na saliva interferem diretamente nas

funções exercidas pela mesma na manutenção da saúde oral e funções como fala,

mastigação e deglutição. As glândulas salivares têm a capacidade de concentrar iodo

e a passagem do

131

I pelos ductos salivares durante a iodoterapia repercute em

alterações salivares após o tratamento devido aos efeitos nocivos da radiação emitida

por esta substância. Objetivo: Este estudo tem por objetivo avaliar os efeitos

colaterais tardios da iodoterapia sobre as glândulas salivares e seu impacto na

qualidade de vida dos pacientes submetidos a esta terapia, e investigar a eficácia da

amifostina como protetor das glândulas salivares aos efeitos deletérios da

iodoterapia. Metodotologia: Cintilografia de glândulas salivares, sialometria e

aplicação do questionário de Qualidade de Vida da Universidade de Washington e

algumas questões elaboradas pelos pesquisadores foram utilizadas para avaliar tanto

os efeitos tardios como o efeito protetor da amifostina aos danos associados a

iodoterapia. Resultados: Em relação aos efeitos colaterais tardios da iodoterapia

verificamos que a idade é um fator importante na função das glândulas salivares,

onde pacientes acima de 45 anos apresentam fluxo salivar não-estimulado e

estimulado menores, mas que pacientes submetidos a iodoterapia apresentam uma

dificuldade de eliminação concentrada principalmente em parótidas verificada tanto

por cintilografia das glândulas salivares como por sialometria. Em relação a

qualidade de vida verificou-se que doses de iodoterapia acima de 150 mCi impactam

em funções associadas com a função salivar como fala, mastigação e deglutição. Na

avaliação do efeito protetor da amifostina nos efeitos deletérios da iodoterapia sobre

as glândulas salivares, nas condições deste estudo, não verificamos eficácia desta

medicação para este propósito com efeitos adversos graves associados à

administração endovenosa da medicação. Conclusão: O presente estudo reforça

teoria de que o principal efeito do

131

I sobre as glândulas salivares resulta em uma

dificuldade de eliminação da saliva produzida em quantidades normais por uma

constrição ductal devido a fibrose periductal induzida pela radiação. Além disso,

estas alterações causam impacto na qualidade de vida e queixas acentuadas

relacionadas à deglutição. O uso da amifostina náo foi eficaz na prevenção dos

efeitos deletérios do

131

I sobre as glândulas salivares no presente estudo. A

administração da amifostina, um medicamento com efeito adverso de hipotensão

potencial, em pacientes em estado de hipotireoidismo deve ser realizada com cautela,

visto que estes pacientes apresentam dificuldade de compensão da pressão diastólica.

SUMMARY

Almeida JP. [Evaluation of adjuvant radioactive iodine therapy side effects on

salivary glands in patients with well-differentiated thyroid carcinoma]. São

Paulo; 2009. [Tese de Doutorado-Fundação Antônio Prudente].

Introduction: Saliva plays important functions in maintaining oral functions.

Qualitative or quantitative saliva alterations can impact on functions as oral health

maintainance, speeking, chewing and swallowing functions. The salivary glands are

able to concentrate iodine and the

131

I passing through salivary ducts, during

radioiodine therapy, results as salivar alterations after treatment due to emission of

radiotion by iodine. Objective: This study aims to evaluate the late side effects of

radioactive iodine therapy (RIT) on salivary glands and its impact on quality of life

of these patients, and to investigate the efficacy of amifostine as salivary gland

protector to iodine side effects. Methods: Salivary gland scintigraphy, sialometry

and the questionnaire of University of Washington Quality of Life and some

questions designed by the researches were used to evaluate the late side effects and

the protector efficacy of amifostine to salivary gland damage associated to RIT.

Reults: About late side effects of RIT, the age was an important factor in the

function of salivary glands, with patients older 45 years having a descreased

unstimulated and stimulated salivary flow. Patients submitted to RIT have more

difficulty to eliminate saliva, mainly from parotids, verified by salivary gland

scintigraphy and sialometry. In relation to quality of life, doses of iodine higher than

150 mCi have impact in salivary functions as speech, chewing and swallowing.

Evaluating the protective effect of amifostine on late effects of RIT on salivary

glands, it was not verified the efficacy of this drug, with serious side effects

associated to endovenous via of administration. Conclusion: The present study

reinforce the theory that the main effect of

131

I on salivary glands results in difficulty

to eliminate the saliva produced, in normal quantities, by a ductal constriction due to

periductal fibrosis induced by radiation. Besides that, these alterations have impact

on quality of life and severe complaints related to swallowing. The amifostine was

not able to prevent side effects of RIT on salivary glands in the present study. The

amifostine administration, a drug with known hipotensive effect, in patients

withdraw thyroid hormone must be done carefully, since these patients have

difficulty to compensate the diastolic blood pressure.

LISTA DE FIGURAS

Figura 1

Regiões de Interesse (ROI).............................................................. 24

Figura 2

Curva de tempo/atividade da concentração do radiotraçador em

uma glândula salivar no período de 30 minutos de cintilografia de

glândula salivar............................................................................... 25

Figura 3

Ilustração da seleção de pontos feita pelo software para realizar o

ajuste exponencial pelo método dos mínimos quadrados e então

calcular T1/2 pós-administração do suco de limão......................... 27

LISTA DE TABELAS

Artigo 1

Tabela 1.1

Description of demographic and treatment variables……………...

Tabela 1.2

Bivariate associations between demographic and treatment

variables and each function domain and composite score of UW-

QOL questionnaire……………………………………………….

Tabela 1.3

Multiple linear regressions with the significant variables on the

bivariate analyses…………………………………………………

Artigo 2

Tabela 2.1

Descriptive analyses of dependent variables……………………..

Tabela 2.2

Univariate analyses associating salivary gland scintigraphy

results with dependent variables………………………………….

Tabela 2.3

Univariate analyses associating sialometry results with

independent variables…………………………………………….

Tabela 2.4

Multiple linear regression with independent variables………....

Artigo 3

Tabela 3.1

Data of five patients who completed one week of treatment with

pilocarpine…………………………………………………………

Artigo 4

Tabela 4.1

Description of clinical variables of both groups pre-treatment..

Tabela 4.2

Description of scintigraphy of salivary glands data in both groups

pre-treatment………………………………………………………

Tabela 4.3

Acute side effects associated to I

131

during RIT…………………..

Tabela 4.4

Amifostine and sialodenitis during RIT……………………...........

Tabela 4.5

Differences between post- and pre-treatment values………...........

Considerações finais

Tabela 5.1

“Scores” médios dos 12 domínios e “score” final dos grupos

amifostina e placebo pré-tratamento................................................

Tabela 5.2

“Scores” médios dos 12 domínios e “score” final dos grupos

amifostina e placebo pós-tratamento...............................................

Tabela 5.3

Diferença entre os valores pós e pré-tratamento dos domínios que

refletem os efeitos colaterais associados a iodoterapia e “score”

final dos grupos amifostina e placebo..............................................

Tabela 5.4

Status pós-tratamento em relação aos domínios associados aos

efeitos colaterais da iodoterapia e “score” final nos grupos

amifostina e placebo.........................................................................

LISTA DE ABREVIATURAS

99m

TcO

Pertecnetato de sódio

CBDT Carcinoma bem diferenciado de tireóide

CGS Cintilografia de glândulas salivares

DRI Dose real injetada

FSE Fluxo salivar estimulado

FSNE Fluxo salivar não estimulado

LI Local da injeção

PDPre Parótida direita pré

PDPos Parótida direita pós

PEPre Parótida esquerda pré

PEPos Parótida esquerda pós

QV Qualidade de vida

ROI Regiões de interesse

SF Solução fisiológica

SDPre Submandibular direita pré

SDPos Submandibular direita pós

SEPre Submandibular esquerda pré

SEPos Submandibular esquerda pós

SPre Seringa pré-injeção

SPos Seringa pós-injeção

UW-QOL University of Washington – Quality of Life

ÍNDICE

1 INTRODUÇÃO

1.1 Câncer de Tireóide...........................................................................................1

1.2 Fisiologia do Iodo nas Glândulas Salivares.....................................................2

1.3 Cintilografia de Glândulas Salivares...............................................................5

1.4 Pilocarpina.......................................................................................................7

1.5 Amifostina........................................................................................................8

1.6 Qualidade de Vida em Pacientes Oncológicos...............................................10

2 OBJETIVOS

2.1 Objetivos Principais.......................................................................................13

2.2 Objetivos Secundários....................................................................................13

3 MATERIAL E MÉTODOS

3.1 Estudo I..........................................................................................................14

3.1.1 Critérios de seleção.........................................................................................14

3.1.2 Critérios de exclusão.......................................................................................15

3.1.3 Divisão dos Grupos.........................................................................................15

3.1.4 Amostra e variáveis coletadas.........................................................................15

3.1.5 Avaliação de dados subjetivos........................................................................16

3.1.6 Avaliação de dados objetivos..........................................................................16

3.1.7 Melhora da xerostomia com o uso de pilocarpina..........................................19

3.2 Estudo II……………………………………..……………………………...20

3.2.1 Critérios de seleção.........................................................................................20

3.2.2 Critérios de exclusão.......................................................................................20

3.2.3 Randomização.................................................................................................20

3.2.4 Avaliação de dados subjetivos........................................................................21

3.2.5 Avaliação de dados objetivos..........................................................................21

4 RESULTADOS

4.1 Estudo I...........................................................................................................29

4.1.1 Clinical predictors of quality of life among patients with initial

differentiated thyroid cancers…………..…………………………...………29

4.1.2 Late side effects of radioactive iodine therapy on salivary gland function

in patients with thyroid cancer………………………………………………46

4.1.3 The use of pilocarpine to treat xerostomia in patients submitted

radioactive iodine therapy: a pilot study…………………………….………63

4.2 Estudo II..........................................................................................................71

4.2.1 Amifostine protection of radioiodine side effects on salivary gland:

a prospective, randomized and double-blind study…………………………71

5 CONSIDERAÇÕES FINAIS.......................................................................89

6 CONCLUSÕES.............................................................................................94

7 REFERÊNCIAS BIBLIOGRÁFICAS........................................................96

ANEXOS

Anexo 1 TCLE estudo I

Anexo 2 Aprovação CEP Fundação Antônio Prudente

Anexo 3 Questionário

Anexo 4 Ficha de avaliação do tratamento com pilocarpina

Anexo 5 TCLE estudo II

Anexo 6 Aprovação CEP Fundação Pio XII

Anexo 7 Tabela de randomização

Anexo 8 Artigo publicado

1 INTRODUÇÃO

1.1 CÂNCER DE TIREÓIDE

A American Cancer Society em 2007 estimou a ocorrência de 33.550 novos

casos de câncer de tireóide nos Estados Unidos em 2007, um número de óbitos de

1530 casos (JAMEL et al. 2008). A maioria dos pacientes com câncer de tireóide

apresenta carcinomas bem-diferenciados (papilifero ou folicular). O tratamento

inicial de escolha é a tireoidectomia total, seguida por mapeamento de corpo inteiro

com

123

I ou

131

I para detecção de doença residual remanescente ou metástases, e

ablação com iodoterapia (

131

I) (MAZZAFERRI 1999). A dose administrada de

131

para terapia ablativa varia de 30

a 150mCi, tornando-se às vezes necessário doses

maiores ou adicionais (NEWKIRK et al. 2000).

A terapia com

131

I é considerada como de grande valor no tratamento

adjuvante de carcinomas bem-diferenciados de tireóide (CBDT). Em geral, os efeitos

colaterais são moderados e autolimitados e complicações graves são raras, tornando

esta modalidade terapêutica de baixo risco (BUSHNELL et al. 1992; ALEXANDER

et al. 1998). Os efeitos colaterais mais comumente relatados durante o tratamento são

náuseas, vômitos, epigastralgia, sialodenites e alteração do paladar. Entretanto, com

altas doses de

131

I, seqüelas graves como leucemia, depressão severa de medula óssea

seguida por hemorragias e complicações infecciosas, pneumonite por radiação e/ou

fibrose pulmonar, embora raramente, têm sido relatadas (BUSHNELL et al. 1992;

ALEXANDER et al. 1998).

1.2 FISIOLOGIA DO IODO NAS GLÂNDULAS SALIVARES

A saliva tem participação significativa na manutenção da função oral através

da ação de proteínas como amilase, imunoglobulinas e lisozimas, bem como através

da lubrificação da cavidade oral facilitando a fala, a deglutição e a sensação de

paladar. A perda ou diminuição do fluxo salivar pode alterar a eficiência destas

funções, resultando assim em morbidade significativa (NEWKIRK et al. 2000). A

capacidade de concentração de iodo radioativo nas glândulas salivares as tornam

vulneráveis durante e após o uso destas substâncias no manejo de pacientes com

CBDT.

As glândulas salivares têm a capacidade de concentrar iodo seletivamente por

razões ainda não bem determinadas. Alguns estudos sugerem que a captação de iodo

nas glândulas salivares, e da mesma forma o pertecnetato de sódio (

99m

TcO

), ocorre

através do sistema de co-transporte de Na

/Cl

, sendo posteriormente secretados

na saliva (MARTINEZ e CASSITY 1985; HELMAN et al. 1987). Estudos mais

recentes mostram por imunohistoquímica a expressão deste sistema de co-transporte

também denominado “Na/I Symporter – NIS” exclusivamente nos ductos salivares

(Jhiang et al. 1998; Vayre et al. 1999). A concentração salivar de iodo varia de 20 a

100 vezes mais que a encontrada no plasma (GOOLDEN et al. 1957; MASON et al.

1967; MAIER e BIHL 1987). É esta habilidade de concentração crítica responsável

pelos danos glandulares quando o

131

I é utilizado.

O principal local de transporte do iodo para a saliva é o epitélio dos ductos

intralobulares das glândulas parótidas. O iodo se difunde através dos capilares

periductais e concentra-se no epitélio ductal, onde é excretado dentro do lúmen

ductal e, finalmente, transportado para a cavidade oral. Tem sido calculado que mais

de 24% de todo o

131

I administrado para terapia de carcinomas de tireóide é perdido

na saliva (MAIER e BIHL 1987; MANDEL e MANDEL 2003), no entanto, há

relatos de que este iodo excretado pela saliva é reabsorvido no trato gastrointestinal,

retornando ao plasma (MAIER e BIHL 1987).

No processo de concentração de iodo radioativo, as glândulas salivares são

expostas aos efeitos deletérios da radiação. Embora todas as glândulas salivares

sejam envolvidas no transporte de iodo radioativo para a saliva, as glândulas

parótidas são as mais ativas e as células serosas parecem ser mais susceptíveis que as

mucosas aos efeitos deletérios da radiação ionizante (MALPANI et al. 1996;

ALEXANDER et al. 1998; CAGLAR et al. 2002; MANDEL e MANDEL 2003).

Esta diferença de sensibilidade à radiação entre células serosas e mucosas não é bem

esclarecida, mas tem sido sugerido que a hipofunção aguda das glândulas salivares

induzida por radiação é atribuída à morte precoce das células serosas como resultado

da ruptura da membrana causada por apoptose. É discutido se as alterações nucleares

que ocorrem são causadas diretamente pela radiação ou indiretamente por outros

mecanismos, incluindo alterações na membrana celular e/ou liberação de enzimas

lizossomais (JENSEN et al. 2003).

A irradiação das glândulas salivares pelo

131

I causa danos endoteliais na

vasculatura glandular (MAIER e BIHL 1987). Um aumento na permeabilidade

capilar resulta na perda de proteínas plasmáticas e eletrólitos para o tecido

intersticial. Simultaneamente, os ductos intralobulares lesados pela radiação perdem

a habilidade de filtrar proteínas plasmáticas para a saliva. Como resultado destes dois

mecanismos, elevação dos valores proteícos na saliva são encontradas

principalmente nas glândulas parótidas (MAIER e BIHL 1987). Elevados níveis de

sódio e cloro também são encontrados na saliva de parótidas devido ao dano ductal

causado pela radiação, o qual perde a capacidade de reabsorver estes eletrólitos

secretados pelas células acinares terminais através do sistema ductal. Além disso, os

níveis de fosfato estão diminuídos devido ao dano das paredes do epitélio ductal

intralobular, o qual falha na sua função normal de transportar fosfato para a saliva

(MAIER e BIHL 1987).

O efeito do

131

I sobre o parênquima e os ductos excretores são independentes

um do outro. Captação anormal de parênquima e função excretória anormal ou

ambos foram observadas com análises utilizando

99m

TcO

(MALPANI et al. 1996).

Inicialmente, a captação de

99m

TcO

pelas glândulas salivares pode estar normal,

mas devido aos danos tardios da parede ductal a excreção de

99m

TcO

é atrasada e

resulta numa aumentada retenção de

99m

TcO

na região glandular. Mais tarde, a

captação diminuída de

99m

TcO

resulta da fibrose vascular causada pelo efeito

destrutivo do

131

I. Devido ao efeito dose-dependente do efeito do

131

I ser tardio a

secreção salivar tende a dimuinir gradualmente com o tempo devido a fibrose

periductal causada pela radiação (MALPANI et al. 1996).

O primeiro caso de sialodenite associado a iodoterapia foi relatado em 1955

por RIGLER e SCANLON e posteriormente outros casos isolados foram relatados

(GOOLDEN et al. 1957; WIESENFELD et al. 1983). Até meados da década de 80

sialodenites associadas a iodoterapia eram relatadas como um efeito colateral raro em

pacientes submetidos a este tipo de tratamento. Em 1984, ALLWEISS et al.

analisaram 87 pacientes que receberam doses terapêuticas de

131

I e verificaram que

sialodenites crônica e/ou aguda ocorriam com mais freqüência do que vinham sendo

relatadas na literatura, acometendo cerca de 11.5% destes pacientes. Posteriormente,

MAIER e BIHL (1987) demonstraram que além de xerostomia, todos os pacientes

submetidos a iodoterapia apresentavam alterações na composição salivar, como o

aumento da atividade de α-amilase e aumento nas concentrações de proteínas e

sódio. Outro estudo com 203 pacientes demonstrou uma incidência de sialodenite

maior que a de 11.5% relatada por ALLWEISS et al. (1984), ocorrendo em 33%

(67/203) dos pacientes. Neste estudo, em 80.6% dos casos (54/67) a glândula

parótida estava envolvida (unilateralmente: 14; bilateralmente: 40), e em 46.3%

(31/67) a glândula submandibular foi afetada (unilateralmente em 8 casos e

bilateralmente em 23). A freqüência de sialodenite mostrou uma associação linear e

dose-dependente. Interessantemente, 27% (55/203) dos pacientes apresentaram uma

perda transitória e dose-dependente de paladar e de olfato (ALEXANDER et al.

1998).

1.3 CINTILOGRAFIA DE GLÂNDULAS SALIVARES

O efeito deletério do iodo radioativo nas glândulas salivares tem sido

demonstrado através de estudos por cintilografia de glândulas salivares (CGS), as

quais demonstram uma incapacidade de secreção salivar no período imediato às altas

doses de radiação (OLMOS et al. 1994). Cintilografias de glândulas salivares

mostram que o dano glandular torna-se mais evidente num período de alguns meses

após o tratamento com a diminuição da produção salivar (OLMOS et al. 1994;

MALPANI et al. 1996), estando estas alterações tardias estreitamente relacionadas

com a dose de iodo radioativo administrada (MALPANI et al. 1996; CAGLAR et al.

2002), e sendo mais evidentes nas glândulas parótidas (CAGLAR et al. 2002).

MALPANI et al. (1996) mostraram que de 33 pacientes tratados com

131

I, 72.7%

apresentaram concentração e excreção anormal de

99m

TcO

. A concentração de

99m

TcO

ou resposta a sialogogo (suco de limão) foi dose-dependente, sendo mais

acentuada com doses maiores de iodo radioativo, além das glândulas parótidas serem

mais afetadas que as glândulas submandibulares. Mais tarde, CAGLAR et al. (2002)

relataram que 69% (31/45) dos pacientes tratados com

131

I apresentavam disfunção

de glândulas salivares avaliada por cintilografia após iodoterapia. 54% (21/39) dos

pacientes relataram queixa de boca seca, geralmente 1 ano após o tratamento

(75.6%), sendo que destes 21 pacientes com queixa clínica de xerostomia, 86%

apresentavam disfunção à CGS.

1.4 PILOCARPINA

Com o intuito de reduzir os danos nas glândulas salivares produzidos pelo

131

I, o uso de sialogogos como sucos ácidos ou ácido cítrico tem sido recomendado

para aumentar a salivação durante a administração de iodo radioativo. Estas medidas

aumentam o fluxo salivar e diminuem o tempo de estase do

131

I nas glândulas

salivares e a concentração de iodo radioativo na saliva. Entretanto, recentemente

NAKADA et al. (2005) mostraram que o estímulo salivar com suco de limão para

diminuir a estase do

131

I nas glândulas salivares deve-se iniciar somente 24 horas

após a administração do

131

I, visto que no período imediato a sua administração a

concentração e a atividade do iodo é muito alta gerando maiores efeitos colaterais

sobre as glândulas salivares (NAKADA et al. 2005). O tempo de trânsito pela

glândula salivar do

131

I também poderia ser diminuído com o uso de drogas

colinérgicas como a pilocarpina e o cevimeline, no entanto, ao contrário de pacientes

submetidos à radioterapia externa, nos quais diversos estudos comprovaram a

eficácia da pilocarpina como um estimulante salivar (LEVEQUE et al. 1993;

HAMLAR et al. 1996; ZIMMERMAN et al. 1997; HORIOT et al. 2000; LEEK e

ALBERTSSON 2002; HADDAD e KARIMI 2002; GORSKY et al. 2004;

MOSQUEDA-TAYLOR et al. 2004), resultados sobre o uso de 5mg de pilocarpina a

cada 8 horas por uma semana após a iodoterapia, publicados recentemente por

SILBERSTEIN em 2008, mostram que a pilocarpina não foi capaz de reduzir a

ocorrência de sialodenite nestes pacientes. ALEXANDER et al. (1998) utilizaram

pilocarpina em pacientes submetidos a iodoterapia, e já não haviam observado

diferença significativa do grau de disfunção salivar em relação aos pacientes que não

fizeram uso da medicação. Entretanto, os autores não descrevem quantos pacientes

fizeram uso do medicamento e, tampouco, apresentam gráficos de comparação entre

os grupos, dificultando assim a análise e a confiabilidade dos dados. Com outro

enfoque ao uso da pilocarpina, AFRAMIAN et al. (2006) avaliaram a eficácia de

uma única dose de 5mg de pilocarpina no fluxo salivar não estimulado e estimulado

em pacientes submetidos a ioterapia há pelo menos 3 meses que apresentavam

sialodenite recorrente e xerostomia. Os resultados deste estudo mostram uma

significante elevação dos fluxos salivares não estimulado e estimulado sem

alterações significantes das pressões sistólica e diastólica, temperatura corporal e

pulso (frequência cardiaca).

1.5 AMIFOSTINA

Outra medicação alternativa sugerida como prevenção aos danos glandulares

causados pelo iodo radioativo é a amifostina. Alguns trabalhos, tanto em modelos

animais como em humanos, têm demonstrado redução significativa dos danos em

glândulas salivares com o uso de amifostina durante a iodoterapia, promovendo uma

significante melhora na qualidade de vida destes pacientes (BOHUSLAVIZKI et al.

1998a, b, 1999; MENDOZA et al. 2004).

Estudos sobre o efeito protetor da amifostina foram iniciados no final da

década de 60, extendendo-se em modelos animais até o final da década de 70

(UTLEY et al. 1976; PRATT et al. 1980; UTLEY et al. 1981; MENARD et al. 1984)

e só nas décadas seguintes iniciaram-se os estudos em humanos.

A amifostina é um composto tiofosfato orgânico, administrado na forma de

uma pró-droga WR-2721 intravenosa ou subcutaneamente, que é metabolizada na

sua forma ativa pela atividade da fosfatase alcalina. Nos tecidos, a amifostina sofre

desfosforilação transformando-se no metabólito ativo – WR-1065 (NEWKIRK et al.

2000; BARDET et al. 2002). A conversão é mais efetiva em meio alcalino dos

tecidos normais que no meio ácido do tecido tumoral. Em adição, a concentração de

fosfatase alcalina é 100 vezes maior no tecido normal que no tecido tumoral. Uma

vez que o metabólito ativo da amifostina torna-se disponível, age capturando radicais

livres de oxigênio, os quais são responsáveis pelos danos teciduais causados pela

radiação (NEWKIRK et al. 2000; BARDET et al. 2002; MANDEL e MANDEL

2003). Esta droga foi originalmente desenvolvida como um agente radioprotetor no

final dos anos 50 como parte do Programa de Desenvolvimento de Drogas

Antiradiação nos Estados Unidos pelo Walter Reed Army Institute of Research and

Development. Dentre os mais de 4000 produtos químicos investigados neste

programa, o grupo aminotiol mostrou-se o mais promissor por sua habilidade de

proteção tecidual contra quimio e radioterapia. A amifostina é o aminotiol mais

extensivamente estudado (BONNER e SHAW 2002).

Estudos clínicos para avaliar a eficácia da amifostina como protetor de

glândulas salivares em pacientes irradiados na região de cabeça e pescoço e como

protetor de diversos órgãos e tecidos em pacientes recebendo quimioterapia

começaram a ser publicados a partir da década de 80 (BLUMBERG et al. 1982;

GLICK et al. 1982; WOOLLEY et al. 1983). O grande desafio enfrentado no uso da

amifostina na prática clínica são os efeitos colaterais associados à droga. O paciente

em uso de amifostina pode apresentar efeitos colaterais como hipotensão, geralmente

com diminuição da pressão sistólica, náuseas, vômitos e mal estar durante as

infusões, geralmente nos primeiros 20 minutos (RADES et al. 2004). A partir destas

dificuldades, SHAW et al. (1999) mostram resultados favoráveis em relação à

administração da amifostina na via subcutânea e KOUKOURAKIS et al. (2000)

publicaram posteriormente um estudo fase II utilizando amifostina subcutânea

durante radioterapia fracionada, mostrando que esta droga adiministrada por via

subcutânea é bem tolerada, reduzindo efetivamente a toxicidade aguda da

radioterapia. Outros estudos mais recentes avaliando a eficácia e melhor

tolerabilidade da amifostina via subcutânea têm sido publicados com resultados

favoráveis a esta via de administração (OZSAHIN et al. 2006; LAW et al. 2007;

ANNÉ et al. 2007).

O uso da amifostina é bem estabelecido pela literatura nos tratamentos de

quimio e radioterapia (BRIZEL et al. 2000; ANTONADOU et al. 2002), mas em

pacientes com câncer de tireóide submetidos a iodoterapia adjuvante os primeiros

dados foram apresentados por Bohuslaviszki et al. em 1998 e mais recentemente por

KIM et al. em 2008. O estudo publicado por BOHUSLAVIZKI et al. (1998b) é um

estudo controlado, duplo cego, com 50 pacientes incluídos, que mostrou uma

redução do dano no parênquima das glândulas salivares causado pela iodoterapia

com o uso da amifostina. O estudo publicado por KIM et al. (2008) é um estudo não

randomizado, com 80 pacientes onde não se verificou os efeitos protetores da

amifostina sobre as glândulas salivares em pacientes submetidos a ioterapia

adjuvante.

1.6 QUALIDADE DE VIDA EM PACIENTES ONCOLÓGICOS

Tradicionalmente, a principal forma de avaliar a evolução de pacientes

oncológicos é a sobrevida baseada no controle tumoral, mas recentemente reconhece-

se cada vez mais que o diagnóstico e o tratamento do câncer pode ter um

significativo impacto na qualidade de vida destes pacientes (TAN et al. 2007). O

objetivo do tratamento oncológico tornou-se não só controlar a doença e aumentar a

sobrevida como também preservar a qualidade de vida (HUANG et al. 2004), e

quantificar as alterações na qualidade de vida (QV) destes pacientes tem sido

considerado de grande importância nos dias atuais (VARTANIAN et al. 2004; TAN

et al. 2007).

Qualidade de vida é definida como a percepção do indivíduo e sua posição na

vida, em um contexto cultural e sistema de valores no qual este indivíduo vive e em

relação aos seus objetivos, expectativas, parâmetros e preocupações (WHOQOL

Group 1993). A Qualidade de Vida relacionada à Saúde se refere a um conceito

multidimensional, o qual compreende a percepção de aspectos negativos e positivos

de pelo menos quatro dimensões: as funções física, emocional, social e cognitiva as

quais podem ser influenciadas pela doença ou o tratamento desta (CREVENNA et al.

2003).

Nos últimos 20 anos um crescente número de estudos tem avaliado a QV

diária como o ponto final na avaliação do impacto da doença e seu tratamento

(DAGAN et al. 2004; VARTANIAN et al. 2006). Entretanto, há relativamente

poucos estudos de QV relacionada à Saúde voltados especificamente para pacientes

com câncer de tireóide (CREVENNA et al. 2003; DAGAN et al. 2004; TAN et al.

2007). A falta de instrumentos específicos para aferir a Qualidade de Vida em

pacientes com câncer de tireóide associada a baixas taxas de mortalidade e

morbidade do tratamento podem explicar o reduzido número de estudos neste campo.

A maioria dos estudos publicados utiliza o questionário SF-36 que é um

instrumento genérico para verificar QV e não possui domínios específicos para

avaliar o impacto de possíveis efeitos colaterais associados ao tratamento. Vários

instrumentos têm sido desenvolvidos para aferir a qualidade de vida em pacientes

com câncer de cabeça e pescoço. Entre eles, o questionário de Qualidade de Vida da

Universidade de Washington é um instrumento validado, de acurácia e

internacionalmente aceito. O uso deste questionário permite a avaliação da QV

relacionada à Saúde e leva a um melhor entendimento das expectativas do paciente

(VARTANIAN et al. 2004). Embora não comumente utilizado em pacientes com

câncer de tireóide, o questionário de Qualidade de Vida da Universidade de

Washington tem um valor preditivo na QV destes pacientes visto que é possível

avaliar pontos que podem estar associados a efeitos colaterais do tratamento como

um todo – cirurgia e iodoterapia.

2 OBJETIVOS

2.1 OBJETIVOS PRINCIPAIS

1. Avaliar os efeitos colaterais tardios da iodoterapia sobre as glândulas salivares

maiores.

2. Testar a eficácia da amifostina em prevenir danos nas glândulas salivares após

o tratamento.

2.2 OBJETIVOS SECUNDÁRIOS

1. Avaliar a qualidade de vida após o término do tratamento de pacientes com

carcinoma bem-diferenciado de tireóide.

2. Avaliar a resposta ao uso da pilocarpina nos pacientes submetidos a

iodoterapia que apresentam queixa clínica de xerostomia.

3. Avaliar a incidência de alterações salivares agudas durante o tratamento com

iodo radioativo.

3 MATERIAL E MÉTODOS

Para alcançarmos todos os objetivos propostos, este trabalho foi dividido em

dois estudos: ESTUDO I – um estudo transversal de carater retrospectivo com coleta

prospectiva da função de glândulas salivares para alcançarmos os objetivos principal

1 e secundários 1 e 2; ESTUDO II – um ensaio clínico, randomizado e duplo cego

para alcançarmos os objetivos principal 2 e secundários 1 e 3.

3.1 ESTUDO I

Todo o Estudo I foi desenvolvido no Hospital A. C. Camargo com a

colaboração dos Departamentos de Cirurgia de Cabeça e Pescoço, para triagem dos

pacientes, e de Imagem - Medicina Nuclear para realização dos exames de CGS.

3.1.1 Critérios de seleção

Pacientes com carcinoma papilífero ou folicular de tireóide, atendidos em

consulta de seguimento no período de 1997 a 2006, submetidos a tireoidectomia total

seguido ou não de iodoterapia adjuvante.

3.1.2 Critérios de exclusão

Pacientes submetidos a radioterapia externa prévia na região de cabeça e

pescoço e pacientes com sintomas prévios de síndrome sicca.

3.1.3 Divisão dos Grupos

Grupo I - pacientes submetidos a tireoidectomia total que não foram submetidos a

131

Grupo II – pacientes submetidos a tireoidectomia total e ao I

131

independente da

dose.

3.1.4 Amostra e variáveis coletadas

Quatrocentos pacientes que preenchiam os critérios de inclusão foram

convidados a participar do estudo durante suas consultas de seguimento. Destes, 184

pacientes aceitaram participar e assinaram o Termo de Consentimento Livre e

Esclarecido (Anexo 1) aprovado pelo Comitê de Ética do Hospital A. C. Camargo

(Anexo 2).

Dos 184 pacientes avaliados dados como idade, gênero, subtipo tumoral,

TNM, estadio clínico, data da cirurgia, esvaziamento cervical, data e dose recebida

na iodoterapia, comorbidades presentes avaliadas pela classificação de risco

cirúrgico da American Society of Anesthesiology (ASA) e o uso de medicação

xerostômica (anti-hipertensivos, antidepressivos e anti-histamínicos) foram coletados

dos prontuários.

3.1.5 Avaliação de dados subjetivos

Os pacientes responderam ao questionário de Qualidade de Vida da

Universidade de Washington, validado em língua portuguesa e disponibilizado para

uso público (VARTANIAN et al. 2006) e a algumas questões elaboradas pelos

pesquisadores visando identificar os efeitos colaterais da iodoterapia sobre as

glândulas salivares sempre antes da coleta dos dados objetivos (Anexo 3).

O questionário de Qualidade de Vida da Universidade de Washington foi

desenhado para que o paciente fosse capaz de respondê-lo sem qualquer ajuda. Desta

forma, o questionário foi aplicado em um dia específico reservado para o estudo e os

pacientes que por algum motivo não se sentiram aptos a responder sozinhos ao

questionário tiveram auxílio do acompanhante para fazê-lo.

3.1.6 Avaliação de dados objetivos

Para avaliação objetiva da função das glândulas salivares os pacientes foram

submetidos a cintilografia de glândulas salivares e sialometria de fluxo salivar, dos

quais estão descritas abaixo as metodologias utilizadas.

9 Cintilografia de Glândulas Salivares

As CGS neste estudo I foram realizados de acordo com o protocolo adotado

pelo Departamento de Imagem – Medicina Nuclear do Hospital A. C. Camargo. Os

pacientes foram instruídos a não ingerir alimentos, não fazer sua higiene oral e não

fumar pelo menos 90 minutos antes do procedimento e tomar 3 copos de água para

garantir uma boa hidratação 30 minutos antes da realização do exame.

Equipamentos utilizados:

1) Gama câmera de um detector (modelo GE StarCam 4000, GE Medical

System, Milwaaukee, WI, EUA).

2) Colimador LEHR (low energy high resolution).

3) Energia 140KeV (janela de 15%).

4) Work Station (GE Entegra, GE Medical System, Milwaaukee, WI, EUA).

Radioisótopo e dose utilizados:

99m

TcO

(pertecnetato de Sódio) fornecido pelo IPEN, CNEN-SP.

2) 10mCi (370MBq) com via de administração endovenosa.

Metodologia do exame:

1) Preparação: aquisição de imagem para a contagem da dose de

99m

TcO

que

seria administrada em imagem estática de 1 minuto, com matriz 128 x 128 W.

2) FASE 1 – Estudo dinâmico de fluxo sanguíneo: foram realizadas 90 imagens

de 1 segundo na projeção anterior, e duração total de 90 segundos, em matriz

128 x 128 W.

3) FASE 2 – Estudo estático das glândulas salivares pré-estímulo: captação de 3

imagens nas projeções anterior, lateral direita e lateral esquerda, nesta

respectiva sequência, no sentido antero-posterior com duração de 3 minutos

cada, aguardando-se 5 minutos após imagem de fluxo sanguíneo, em matriz

de 256 x 256 W.

4) Estímulo: fornecido ao paciente por 5 minutos um comprimido de 1g de ácido

ascórbico (Cewin®, Sanofi-Aventis, Brasil) para dissolução na cavidade oral

com finalidade de estimular o fluxo salivar, e realizado neste intervalo o

exame de sialometria de fluxo salivar.

5) FASE 3 – Estudo estático das glândulas salivares pós-estímulo: captação de 3

imagens (anterior, lateral direita e lateral esquerda) com duração de 3 minutos

cada, em matriz de 256 x 256 W.

6) Ao final foi realizada a contagem da dose residual de

99m

TcO

na seringa após

a administração e do local da injeção, em imagem estática de 1 minuto de

duração cada, com matriz 128 x 128 W.

Processamento e quantificação das imagens adquiridas:

1) Criação de regiões de interesse (ROIs) nas imagens de seringa pré-injeção

(SPre), seringa pós-injeção (SPos), local da injeção (LI) e as imagens estáticas

com projeção anterior pré e pós estímulo, nas topografias das glândulas

salivares [glândulas parótidas direita (PD) e esquerda (PE) e

submandibular/sublingual direita (SD) e esquerda (SE)].

2) Quantificação do número de contagens em cada ROI (SPre, SPos, LI, PDPre,

PEPre, SDPre, SEPre, PDPos, PEPos, SDPos, SEPos).

3) Cálculo da captação e eliminação em cada glândula salivar pelas seguintes

fórmulas:

Dose real injetada (DRI) = SPre – SPos – LI

% Captação (CPD) = PDPre * 100 / DRI

% Eliminação (EPD) = PDPos * 100 / CPD

9 Sialometria de fluxo salivar

A metodologia de sialometria utilizada foi baseada no método descrito por

KOSEKI et al. (2004) e os parâmetros de normalidade de fluxo salivar total adotados

foram de 0.3 ml/min para o fluxo não estimulado e 1.5 ml/min para o fluxo

estimulado publicados por JENSEN et al. (2003). Os pacientes foram instruídos a

não ingerir alimentos, não fazer sua higiene oral e não fumar pelo menos 90 minutos

antes do procedimento.

Fluxo salivar total não estimulado (FSNE)

1 Coleta do fluxo salivar total não estimulado em um tubo Falcon de 15ml, no

período de 5 minutos. O total de saliva coletado em ml foi dividido por 5

obtendo-se assim o fluxo salivar em ml/min.

2 Fluxo salivar total estimulado (FSE)

Um comprimido de 1g de ácido cítrico foi fornecido ao paciente para

dissolução contínua em cavidade oral durante 5 minutos e o fluxo salivar total

estimulado coletado em um tubo Falcon de 15ml. O total de saliva coletado em ml

foi dividido por 5 obtendo-se assim o fluxo salivar em ml/min.

3.1.7 Melhora da xerostomia com o uso de pilocarpina

Aos pacientes que apresentaram queixa clinica de xerostomia, alteração de

fluxo salivar à sialometria e na análise visual da CGS apresentaram glândula residual

funcionante, e não apresentaram contra-indicações ao uso da pilocarpina (portadores

de asma, hipertensão arterial, problemas cardíacos e glaucoma de ângulo fechado),

foi entregue um frasco com 90 capsulas de 5mg de pilocarpina e instruções para uso

3 vezes ao dia, com o objetivo de avaliar uma possível eficácia terapêutica nos casos

de xerostomia. Os pacientes preencheram um relatório durante a primeira semana de

uso e avaliação subjetiva da eficácia da pilocarpina foi realizada (Anexo 4).

3.2 ESTUDO II

Todo o Estudo II foi desenvolvido no Departamento de Medicina Nuclear da

Fundação Pio XII – Hospital do Câncer de Barretos. Todos os pacientes incluídos no

estudo assinaram o Termo de Consentimento Livre e Esclarecido aprovado pelo

Comitê de Ética da Instituição (Anexos 5 e 6).

3.2.1 Critérios de seleção

Pacientes com carcinoma papilífero, folicular ou células de Hurtle de tireóide,

submetidos a tireoidectomia total que seriam submetidos a terapia complementar

com iodo radioativo pela primeira vez.

3.2.2 Critérios de exclusão

Pacientes submetidos previamente a qualquer dose de iodo radioativo,

pacientes submetidos a radioterapia externa prévia na região de cabeça e pescoço,

pacientes com sintomas prévios de síndrome sicca e pacientes que apresentassem

contra-indicações para o uso da amifostina (pacientes com hipersensibilidade ao

aminotiol, hipotensos, em estado de desidratação, com insuficiência renal ou

hepática, com idade superior a 70 anos, mulheres grávidas ou em período de

lactação).

3.2.3 Randomização

Os pacientes foram randomizados em dois grupos através de uma tabela de

números aleatórios com 60 números, onde estabeleceu-se que os números pares

corresponderiam aos pacientes que comporiam o grupo placebo e os números

ímpares aos pacientes que comporiam o grupo estudo/amifostina. Toda a

randomização foi duplo-cega contando com uma única pessoa responsável pela

randomização, preparo da medicação e quebra do sigilo caso necessário (Anexo 7).

Ao grupo placebo foi administrado 1ml SF 0,9% estéril por via subcutânea e ao

grupo amifostina foi administrado 200mg/m

amifostina (Ethyol®, Shering Plough

do Brasil) diluída em 1ml SF 0,9% estéril por via subcutânea, 15 minutos antes da

ingestão do iodo radioativo. Pressão arterial foi aferida antes e 30 minutos após a

infusão em todos os pacientes, e todos os pacientes foram acompanhados por equipe

especializada.

3.2.4 Avaliação de dados subjetivos

Os pacientes foram submetidos ao questionário de qualidade de vida, UW

QOL – University of Washington Quality of Life validado em língua portuguesa e

disponibilizado para uso público (VARTANIAN et al. 2006) - em dois tempos

diferentes, antes de iniciarem a iodoterapia e 3 meses após o término da iodoterapia

(Anexo 3).

3.2.5 Avaliação de dados objetivos

Para avaliação objetiva da função das glândulas salivares os pacientes foram

submetidos a exames de cintilografia de glândulas salivares e sialometria de fluxo

salivar imediatamente antes de iniciarem iodoterapia e 3 meses após o término da

iodoterapia.

9 Cintilografia dinâmica de glândulas salivares

As cintilografias foram realizadas de acordo com o protocolo adotado pelo

departamento de Medicina Nuclear da Fundação Pio XII – Hospital do Câncer de

Barretos e sob supervisão do Dr. Euclides Timóteo da Rocha.

Através da administração intravenosa de pertecnetato, obtido a partir da

eluição diária de geradores de tecnécio fornecidos pelo IPEN (Instituto de Pesquisas

Energéticas e Nucleares) em São Paulo, foram realizadas mensurações de fluxo

sangüíneo, inicialmente, e posteriormente acúmulo e excreção. Os pacientes tinham

conhecimento com antecedência de como era o procedimento, e as dúvidas residuais,

quando presentes, eram esclarecidas. Para todos os pacientes foi solicitado jejum de

2 horas antes da realização do exame. Após esclarecimento de dúvidas, o paciente

era conduzido à sala da gama-camara, posicionado deitado na mesa de exames com a

cabeça e região cervical sob o detetor, região cervical livre de objetos atenuantes,

nariz centralizado e cabeça levemente extendida, e um cateter inserido em um vaso

superficial do membro superior onde foram administrados 370MBq (10mCi) de

99m

Tc-pertecnetato com aquisição de imagens imediatamente após a infusão.

As aquisições das imagens foram realizadas em três equipamentos de dois

detetores (MILLENNIUM VG e MILLENNIUM MG, General Electric Medical

System; e FORTE, Philips), equipados com colimadores de alta resolução. Foi

utilizado como protocolo padrão aquisição com uma imagem a cada 3 segundos no

primeiro minuto, e a cada 30 segundos durante 30 minutos empregando-se uma

matriz de 128x128 pixels, e magnificação de 1,5 vezes. Imagens estáticas não foram

obtidas ao longo do estudo para evitar interrupção da aquisição dinâmica. Além

disto, deve ser acrescido que o estímulo com suco de limão foi realizado aos 20

minutos do início do estudo com a finalidade de provocar secreção salivar.

Interpretação das imagens de medicina nuclear:

Tanto aquisições estáticas quanto as dinâmicas podem ser realizadas para

avaliar as glândulas salivares, no entanto, no presente estudo apenas as dinâmicas

foram obtidas. Os exames foram analisados por um único médico nuclear, cego para

os dados clínicos. Estes foram avaliados quanto a movimentações, contaminações ou

outras alterações artefatuais que pudessem trazer prejuízo às analises visual ou semi-

quantitativa. No campo visual observamos as glândulas parótidas e submandibulares,

cavidade oral que captam o radiotraçador (Figura 1). Os achados cintilograficos em

glândulas normais são aumento agudo e simétrico da captação, demonstrado pelas

curvas de tempo/atividade, com queda abrupta, fase excreção, após estímulo com o

sialagogo, e, subseqüente retorno da captação do radiotraçador pela glândula (Figura

2).

Para realizar as medidas de atividade em função do tempo, porcentagem de

captação (uptake) em função do tempo, fração de excreção, atividade pré-

administração do suco de limão, atividade pós-administração do suco de limão,

porcentagem de captação pré-administração do suco de limão, porcentagem de

captação pós-administração do suco de limão e T

1/2

após-administração do suco de

limão para parótidas direita e esquerda, e submandibulares/sublinguais direita e

esquerda foi desenvolvido software em ambiente de desenvolvimento MATLAB

versão 7.0.0.19920-R14.

O algoritmo empregado pelo software inicia solicitando definição das

Regiões de Interesse (ROI) referentes a cada glândula em estudo (Figura 1).

Legenda: À esquerda superiormente temos a delimitação da parótida direita e à esquerda

inferiormente a submandibular direita, à direita superiormente temos a parótida esquerda e à direita

inferiormente a submandibular esquerda.

Figura 1 - Regiões de Interesse (ROI).

Após definição das ROI é apresentado um gráfico de contagem em função do

tempo para a parótida direita com objetivo de definir o instante da administração do

suco de limão (Figura 2). A partir desta curva é feita a derivada primeira no software

e então é determinado o momento da injeção que serve como referência para

quantificação da porcentagem de captação pré-administração do suco de limão e pós-

administração do suco de limão.

Figura 2 - Curva de tempo/atividade da concentração do radiotraçador em uma

glândula salivar no período de 30 minutos de cintilografia de glândula salivar.

O programa fornece também o momento em que a derivada primeira da curva

acima sofre inversão abrupta para auxiliar a definição do momento exato da

administração do suco de limão.

Uma vez definido e informado ao programa este momento, o programa faz o

cálculo das variáveis: atividade (em μCi), uptake (em %) e T

1/2

(em min) pós-

administração do suco de limão. A primeira é feita através da equação:

()

calibraçãodefatorROInacontagensCiA

⋅

onde o fator de calibração ó obtido experimentalmente para cada câmara de

cintilação através de teste de sensibilidade plana do sistema [TECDOC 6.02/IAEA].

A expressão para este fator de calibração é:

adesensibilid

calibraçãodefator

⋅

3037

1000

onde o número 30 refere-se ao tempo por frame e a sensibilidade é expressa em

contagens/MBq (contagens por megaBequerel).

A variável porcentagem de captação é calculada através da equação:

[]

()

Ciinjetadaatividade

calibraçãodefatorROInacontagens

Ciinjetadaatividade

CiA

μμ

⋅

==%

A fração de excreção é obtida pela equação:

[]

[

]

[

]

[]

min2

min2min2

pré

póspré

−

onde

[]

min2 pré

U é a média da porcentagem de captação calculada sobre os frames a

partir de 3 minutos que antecedem a administração do suco de limão, durante um

intervalo de tempo de 2 minutos e

[

]

min2 pós

U corresponde à média da porcentagem

de captação calculada sobre os frames a partir de 3 minutos após a administração do

suco de limão, durante um intervalo de tempo de 2 minutos.

A variável T

1/2

pós-administração do suco de limão é obtida fazendo-se o

ajuste exponencial pelo método dos mínimos quadrados ao subconjunto de pontos da

curva de contagens em função do tempo, obtido tomando-se o intervalo

correspondente do máximo até o mínimo subseqüente (Figura 3).

A equação ajustada é:

(

)

máx

eCtC

⋅−

⋅=

onde C

máx

é a contagem máxima, λ é a constante de eliminação e t o tempo.

CONTAGENS EM FUNÇÃO DO TEMPO

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0

TEMPO (min)

CONTAGENS NA ROI

momento 1

momento 2

INTERVALO DE TEMPO UTILIZADO PARA O AJUSTE

EXPONENCIAL NO MOMENTO 2

INTERVALO DE TEMPO UTILIZADO PARA O AJUSTE

EXPONENCIAL NO MOMENTO 1

Figura 3 - Ilustração da seleção de pontos feita pelo software para realizar o ajuste

exponencial pelo método dos mínimos quadrados e então calcular T

1/2

pós-

administração do suco de limão.

Após ajuste exponencial T

1/2

é calculado pela equação:

693,0

2/1

=T , onde λ é a constante do expoente do ajuste exponencial.

9 Sialometria de fluxo salivar

A metodologia de sialometria utilizada foi a mesma descrita no Estudo I

baseada no método descrito por KOSEKI et al. (2004) com parâmetros de

normalidade de fluxo salivar total adotados foram de 0.3 ml/min para o fluxo não

estimulado e 1.5 ml/min para o fluxo estimulado publicados por JENSEN et al.

(2003). Os pacientes também foram instruídos a não ingerir alimentos, não fazer sua

higiene oral e não fumar pelo menos 90 minutos antes do procedimento.

9 Observações

Este estudo começou a ser desenvolvido no Departamento de Medicina

Nuclear do Hospital Samaritano em São Paulo. Entretanto, dois pacientes

apresentaram efeitos colaterais sérios e quebrando o duplo-cego para relatar o

ocorrido ao CEP constatamos que os dois pacientes eram do grupo amifostina. No

total foram incluídos quatro pacientes nesta fase do estudo, mas infelizmente após o

ocorrido a pesquisadora colaboradora no Hospital Samaritano não considerou

prudente continuarmos o estudo, mesmo com parecer favorável do CEP ao

prosseguimento, e o estudo foi interrompido. No Hospital A. C. Camargo não foi

possível a realização do estudo por dificuldades institucionais relacionadas com a

recém-inaugurada unidade de iodoterapia.

4 RESULTADOS

4.1 ESTUDO I

Os resultados do estudo I estão descritos em artigos publicados e submetidos

para publicação.

4.1.1 Artigo 1: Clinical predictors of quality of life among patients with initial

differentiated thyroid cancers

Juliana Almeida, DDS, MSc; José Guilherme Vartanian, MD, PhD; Luiz Paulo

Kowalski, MD, PhD.

Department of Head and Neck Surgery and Otorhinolaryngology, Hospital A. C.

Camargo, São Paulo, Brazil.

Artigo publicado em Arch Otolaryngol Head Neck Surg 2009; 135: 342-6. (Anexo

Abstract

Background: Patients with differentiated thyroid carcinomas (DTC) usually present

a good prognosis with overall survival rates over 90%. Traditionally, the success of

the treatment of cancer patients has been evaluated by the survival time. Recently, it

has been observed that the diagnosis and treatment of cancer have also a strong

impact on the quality of life (QOL) of these patients. This study aims to assess the

QOL in DTC patients and its potential clinical predictors.

Methods: One hundred

and fifty four patients submitted to thyroidectomy from 1997 to 2006 were evaluated

through the Brazilian-Portuguese validated University of Washington - Quality of

Life Questionnaire.

Results: Patients under or equal 45 years had better recreation

score than patients older than 45 years (p=0.036). Of the 154 patients, 38 patients

were submitted to neck dissection. Patients submitted to modified radical neck

dissection reported worse scores on chewing and shoulder pain than patients only

submitted to selective paratracheal lymph node dissection or without neck dissection

(p=0.003 and p=0.004, respectively). Patients that received more than 150mCi

reported significantly worse scores to pain, swallowing, chewing, speech, taste,

anxiety and composite score. Comorbidities evaluated by ASA classification showed

statistical significant impact on recreation, activity, speech, saliva and composite

score (p=0.015; p=0.046; p=0.020; p=0.011 and p=0.008 respectively). In a

multivariate analysis radioactive iodine therapy (RIT) is the only variable associated

with a worse composite score (p=0.003).

Conclusions: These results show that

although the QOL after treatment in thyroid cancer patients can be considered good

for most patients, those patients submitted to RIT with doses higher than 150mCi are

particularly at risk for poor quality of life and therefore may need more intensive

follow up and treatment.

Keywords: thyroid cancer, radioiodine therapy, quality of life.

Introdution

Differentiated thyroid cancer (DTC) patients in general have a very good

prognosis, and the overall long-term survival rate is higher than 90%, with variations

among subsets of patients.

1-2

In DTC surgery is the therapy of choice. Surgical

options include lobectomy with istimectomy or total thyroidectomy with or without

neck lymph node dissection. The choice of procedure is influenced by well-defined

prognostic factors. Ablative surgery of the thyroid and possible neck disease, with

post-operative radioactive iodine treatment (RIT) result in prolonged survival but

may lead to voice alterations, dysfagia, sialodenitis, taste disturbance and

xerostomia.

3-5

Traditionally, the main outcome measure in oncologic patients has long been

survival, based on tumor control, but recently it has been increasingly recognized

that the diagnosis and management of cancer can have a major impact on every

aspects of a patient’s quality of life (QOL).

The aims of cancer treatment became

not only to increase survival but also to preserve quality of life

and measuring these

changes has been considered to be of paramount importance.

1,6

Quality of life (QOL) is defined as an individual’s perceptions of his or her

position in life, in the context of the culture and value systems in which he or she

lives and in relation to his or her goals, expectations, standards and concerns

(WHOQOL Group 1993). The Health-Related Quality of Life (HR-QOL) refers to a

multidimensional concept which encompasses perception of both negative and

positive aspects of at least the four dimensions of physical, emotional, social and

cognitive functions which could be influenced by the disease or its treatment.

Several instruments have been developed to assess QOL in patients with head and

neck cancer. Among them, the University of Washington Quality of Life (UW-QOL)

questionnaire is a validated, accurate, and internationally accepted survey instrument.

The use of such questionnaire allows evaluation of HR-QOL and leads to better

understanding of patient’s expectations.

In the last 20 years, an increasing number of studies have measured QOL as

an endpoint in the evaluation of the impact of the disease and its treatment on the

patient’s daily life.

6,8

However, there have been relatively few HR-QOL studies

looking specifically into thyroid cancer patients.

1,7,8

The aims of this study are to

assess the QOL in DTC patients and evaluate if different modalities of treatment can

interfere in the QOL of these patients.

Patients and methods

Design

A cross-sectional analysis of adults patients with initial DTC treated with

total thyroidectomy and submitted or not to adjuvant radioiodine therapy (RIT) from

1997 to 2006 at a single Tertiary Cancer Institution was performed. Patients

submitted to prior head and neck radiation or with Sicca Syndrome’ symptoms were

excluded. The study was approved by the institutional ethics committee and all

patients signed an informed consent form.

The patients were invited to participate of this study in their follow-up

medical consultation. All of them had normal thyroid hormone levels, and patients

from 4 months to 10 years since the end of treatment were included, with a median

time of 2 years post-treatment. The independent variables were age, gender, time

since treatment, RIT dose, neck dissection, and comorbidities. The dependent

variables were 13 QOL scales from the UW-QOL questionnaire.

Sample

Four hundred patients that completed the inclusion criteria were invited to

participate of this study. Of those, 184 patients agreed to participate and 154

completed the questionnaire and had clinical stages I and II tumors. A total of 137

(89%) were female and 17 (11%) were male and the mean age was 46.9 and the

median age 46 years (21y – 87y). All patients were submitted to a total

thyroidectomy, and 38 patients were also submitted to a neck dissection of levels II-

IV (2 patients), II-VI (9 patients) and level VI (27 patients). One hundred fifty one

patients had papillary carcinoma and 3 patients had follicular carcinoma. The clinical

stages were 85% of tumors in stage I and 15% in stage II. Ninety three (60%)

patients were submitted to RIT and the median doses was 130mCi (30 – 700mCi).

Seventy three patients received doses up to 150 mCi and 20 patients received doses

higher than 150mCi. According comorbities the ASA classification was used and it

was possible to collect data from 137 patients. Thirty eight patients were classified as

ASA I, 97 patients as ASA II and 2 patients as ASA III. The data are summarized in

the Table 1.1.

Measures

Demographic measures included age in years (≤ or > 45 years) and gender.

The age of 45 years was used as a reference due to its important prognostic value in

DTC patients.

The classification to neck dissection was paratracheal (level VI), radical

(level II-IV) and extend radical (level II-VI). At the analysis these patients were

grouped as none (no neck dissection), paratracheal (neck dissection of level VI) and

radical (neck dissection of level II-IV and level II-VI).

Many studies have discussed that radioactive iodine effects are dose-

dependent and a recent study of our group showed that doses higher than 150mCi

have more side effects on salivary glands. In this way, we categorized the variable

RIT in patients that were not submitted to RIT, patients that received up to 150mCi

and those that received more than 150mCi.

Time since treatment was measured in months and categorized into 12

months or less and more than 12 months.

The American Society of Anesthesiologist’s physical status classification

(ASA), which is graded in: I – healthy patients, no medical problems, II – mild

systemic disease, III – severe systemic disease but not incapacitating, IV – severe

systemic disease that is constant threat to life, and V – moribund, not expected to live

24 hours irrespective of operation, was used to grade the comorbidities of the

patients and to associate them with the quality of life of these patients. See details on

Table 1.1.

Quality of life assessment

A Brazilian-Portuguese version of the University of Washington Quality of

Life (UW-QOL) questionnaire validated by Vartanian et al

was used. The UW-QOL

questionnaire was designed as a self-reported scale and for this reason the patients

answered it by themselves. Patients that did not feel able to answer the UW-QOL

questionnaire alone had help of their companion. The UW-QOL questionnaire was

applied during the year of 2006 in days reserved only to this study.

The questionnaire consists of 12 questions that evaluate the following

domains: pain, appearance, activity, recreation, chewing, swallowing, speech,

shoulder, taste, saliva, humor and anxiety and the score vary from 0 to 100, with the

score 100 indicating the best function. The composite score is the mean of the scores

of all 12 domains. There is a general agreement that a composite score between 75-

100 has a little impact on the QOL, a score between 50-74 has a relative impact on

the QOL, and a composite score under 50 has an important impact on the QOL.

Three general questions evaluate the global QOL and the HR-QOL. We scored the

individual domains according to the UW-QOL guidelines. Composite score was

calculated as the mean of the domains scores.

Statistical Analyses

Statistical analysis was performed using version 15.0 of the SPSS statistical

program (SPSS Inc, Chicago, III) for Windows. A descriptive analysis of the results

was performed. Bivariate analyses were conducted comparing each of the

independent variables of age, gender, neck dissection, RIT, time since treatment and

comorbidities to each of the 13 QOL scales on the UW-QOL questionnaire using

non-parametric Mann-Whitney or Kruskal-Wallis tests. To determine significant

predictors of QOL controlling for one another, multivariate analysis was conducted

using multiple linear regression.

Results

In answering the UW-QOL global questions on overall health, 94.4% of

patients reported that their health was the same or better than it was prior to

treatment, 83.9% of patients reported good HR-QOL, and 83.3% of patients reported

good general QOL. There were no significant differences in these global questions

regarding age, gender, RIT, neck dissection or comorbidities. The median composite

score was 93.05 (53.5 – 100) which is associated with a good quality of life.

Bivariate Analyses

Evaluating demographic variables, age had impact on the recreation domain,

with patients older than 45 years showing worse score than younger patients

(p=0.043). To the other domains age did not have significant association. In the same

way, the gender did not have impact on any domain (Table 1.2).

RIT had impact on many domains and doses higher than 150 mCi had a

strong association with worse scores in several domains, as pain (p=0.045),

swallowing (p=0.028), chewing (p < 0.001), speech (p=0.004), shoulder (p=0.037),

taste (p=0.006), anxiety (p=0.004) and composite score (p=0.012). The patients

submitted to neck dissection from level II-VI had significant worse scores to

chewing (p=0.003) and shoulder (p=0.004) domains. The time since treatment was

not associated with worse scores in any domain.

Patients classified as ASA II and III had worse scores in activity (p=0.046),

recreation (p=0.015), speech (p=0.020), saliva (p=0.011) domains and in the

composite score (p=0.008). All these data are summarized in the Table 1.2.

Multivariate Analyses

To conserve power and because gender and time since treatment were not

significant in the bivariate analyses, they were omitted from the multivariate

analyses. Variables with p value up to 0.250 were considered in multiple linear

regression to determine the greatest predictor of QOL in thyroid cancer patients

controlling for one another.

RIT was the strongest predictor factor affecting many domains as chewing,

speech, taste, saliva and anxiety. It was the only variable that influenced the

composite score. Comorbidities measured by ASA classification was the second

predictor to worse QOL affecting several domains as recreation, speech and saliva.

Neck dissection affected chewing and shoulder, and age affected recreation. The data

are summarized in Table 1.3 with the value of unstandardized coefficient B and each

p value.

Discussion

At this study, in univariate as well as in multivariate analysis the greatest

predictor of quality of life in thyroid cancer patients was RIT doses with higher

dosages showing decreased QOL through the composite score. The composite score

shows the impact of all domains evaluated and worse scores in specific domains will

reflect at the final score. Functions as taste, speech, chewing and swallowing are

strongly associated to RIT salivary gland effects as it is seen through the association

between RIT and these domains in the UW-QOL questionnaire. Until now, in our

literature review, none of published studies showed the impact of RIT or doses of

radioactive iodine in the thyroid cancer patients’ quality of life. This is an important

finding, since that the indication of RIT should also consider the late effects of the

treatment.

The side effects of RIT are well recognized, and in general are mild and self-

limited and severe complications are rare enough that the benefit of therapy typically

outweighs its risk.

14,15

The common acute side effects reported are nausea, vomiting,

epigastralgia, taste disturbance and sialodenitis

, and the late side effects normally

restrict to the salivary glands as sialodenitis and xerostomia.

Recent findings of our

group reinforce the hypothesis of Maier and Bihl (1987)

that patients submitted to

RIT have an impairment to drain the saliva and it reflects as clinical dysphagia.

Considering that many of patients with differentiated thyroid cancer are

submitted to RIT, the impact of those specific side effects and those resulting from

the surgical procedure on the quality of life of such patients were not previously

extensively described. There have been relatively few and recent HR-QOL studies

looking specifically into thyroid cancer patients.

1-2,7-8,17-20

The paucity of specific

instruments to assess the QOL of thyroid cancer patients associated to low mortality

and morbidity rates of the treatment can explain so few studies in this field.

The majority of the published studies uses the SF-36 that is a generic QOL

instrument and do not have specific domains to evaluate the impact of possible side

effects of the treatment. The UW-QOL questionnaire, while not commonly used

among thyroid cancer patients, has value in predicting QOL among these patients

since it makes possible to evaluate points that can be related to side effects of the

surgery and RIT.

The main post-operative complications of thyroidectomy are vocal cord palsy

due to dysfunction of the recurrent laryngeal nerve and hypocalcemia. Neck

dissection and paratracheal lymph node dissection when associated with total

thyroidectomy were significantly associated with transitory and permanent

hypocalcemia.

12-13

Besides that, swallowing changes, and occasional dysphagia are

sequelae reported after thyroid resection, even long time after the surgical

procedure.

Interesting, the neck dissection was associated to chewing function instead of

swallowing function, what is commonly reported at the literature due to the injury of

recurrent nerve. As expected neck dissection affected the shoulder domain of QOL

instrument.

Pre-existent comorbidities are associated to a decreased recreation, what was

expected, and domains as speech and saliva. Worse scores of these last domains

associated to the presence of comorbidities probably can be explained by the intake

of some medications that can interfere with the salivary flow.

To our knowledge there is only one study that evaluated the impact of the

resulting side effects of surgical and radioactive iodine on such patients. This study

used an UW-QOL questionnaire adapted and not validated.

The authors evaluated

20 thyroid cancer patients and reported that patients older than 45 years had worse

scores to general health, appearance and chewing, but did not show association of

RIT or neck dissection with any domain.

Different from data of Dagan et al (2004)

our patients reported good general

QOL, with a light impact of the treatment on their health QOL. However, in our

study patients older than 45 years had worse recreation score, and pre-existent

comorbidities had impact on activity, recreation, speech, saliva. The great impact on

the QOL with specific domains was the doses of RIT. Patients submitted to doses

higher than 150mCi had many domains affected as pain, swallowing, chewing,

speech, taste, anxiety and composite score. Morbidities of the surgery are detected in

chewing and shoulder functions. The time since treatment and gender were not

associated with alterations on the QOL.

These results reveal that in spite of thyroid cancer patients have a good

general QOL there is a subset of patients that live with some comorbidities of the

cancer treatment. The doses of RIT can impact on specific activities in daily life of

these patients. The impacts of RIT on specific functions had not been assessed and

reported at the literature until this moment, and more studies are needed to confirm

these findings. Certainly this study has some limitations, since it is a cross-sectional

study and there is neither a baseline QOL before the treatment nor a follow up over

the time. Evaluation of QOL in different points of time since treatment could be

another limitation, but at the analysis it seems not influence the results. Prospective

studies associating videofluoroscopy to evaluate the different phases of swallowing

and salivary gland function studies with patients receiving more than 150mCi can

contribute to clarify these findings.

Table 1.1 - Description of demographic and treatment variables.

Total N Percent

≤ 45y

> 45y

154

47%

53%

Gender

Male

Female

154

137

11%

89%

RIT

None

≤ 150 mCi

>150 mCi

154

40%

47%

13%

Neck dissection

None

Paratracheal

Radical

154

116

75%

17%

Clinical Sta

154

131

85%

15%

ASA

III

137

28%

71%

Table 1.2 - Bivariate associations between demographic and treatment variables and each function domain and composite score of UW-

QOL questionnaire*.

Pain Appearance Activity Recreation Swallowing Chewing Speech Shoulder Taste Saliva Humor Anxiety Composite Score

Age

≤ 45y

> 45y

94,52

90,12

p Value

0,736 0,257 0,291

0,043

0,192 0,566 0,894 0,898 0,148 0,226 0,327 0,256 0,056

Gender

Male

Female

p Value

0,058 0,091 0,449 0,825 0,113 0,893 0,831 0,108 0,312 0,423 0,549 0,773 0,051

RIT

None

≤ 150 mCi

> 150 mCi

86,48

88,01

76,25

95,92

96,84

90,10

98,36

99,32

87,5

98,38

98,64

91,75

89,62

85,89

71,70

96,72

94,55

85,05

88,03

89,58

76,85

91,56

91,82

84,03

p Value 0,045

0,562 0,121 0,519

0,028 < 0,001 0,004 0,037 0,006

0,196 0,647

0,004 0,012

Neck dissection

None

Paratracheal

Radical

98,28

98,15

94,00

86,80

90,15

60,73

p Value

0,860 0,154 0,765 0,553 0,321

0,003

0,329

0,004

0,829 0,941 0,193 0,094 0,563

Time since Tx

≤ 12 m

> 12 m

p Value

0,877 0,610 0,742 0,195 0,721 0,639 0,495 0,569 0,576 0,202 0,136 0,712 0,555

ASA

III

91,45

85,57

75,00

94,08

92,27

62,50

97,39

98,64

83,50

95,66

90,11

67,00

93,20

90,02

83,37

p Value

0,241 0,153

0,046 0,015

0,126 0,777

0,020

0,335 0,345

0,011

0,468 0,329

0,008

*UW-QOL – Universitiy of Washington Quality of Life.

** Mean values for statistical significant variables are shown above p values.

Table 1.3 - Multiple linear regressions with the significant variables on the bivariate analyses.

Pain

Appearance

Activity

Recreation

Swallowing

Chewing

Speech

Shoulder

Taste

Saliva

Humor

Anxiety

Composite

Score

Age

≤ 45y

> 45y

- - -

0.028

(-5.899)

- - - - - - - - -

RIT

None/≤ 150 mCi

> 150 mCi

- - - - -

0.001

(-9.358)

0.016

(-4.705)

0.004

(-10.889)

0.010

(-10.925)

0.049

(-10.960)

0.003

(-7.182)

Neck dissection

None/Paratracheal

Radical

- - - - -

0.027

(-7.700)

0.006

(-22.205)

- - - - -

ASA

I/II

III

- - -

0.013

(-27.560)

- -

0.004

(-15.384)

- -

0.041

(-23.786)

- - -

The values are the p Value and the B value to the confidence interval of 95%.

References

1- Tan LGL, Nan L, Thumboo J, Sundram F, Tan LKS. Health-related quality of

life in thyroid cancer survivors. Laryngoscope 2007; 117: 507-10.

2- Huang SM, Lee CH, Chien LY, Liu HE, Tai CJ. Postoperative quality of life

among patients with thyroid cancer. J Advanced Nursing 2004; 47: 492-99.

3- Mandel SJ, Mandel L. Radioactive iodine and the salivary glands. Thyroid

2003; 13: 265-71.

4- Pedro Netto I, Fae A, Vartanian JG, Barros APB, Correia LM, Toledo RN et

al. Voice and vocal sef-assessment after thyroidectomy. Head Neck 2006; 28:

1106-14.

5- Lombardi CP, Raffaelli M, D’Alatri L, Marchese MR, Rigante G et al. Voice

and swallowing changes after thyroidectmony in patients without inferior

laryngeal nerve injuries. Surgery 2006; 104: 1026-34.

6- Vartanian JG, Carvalho AL, Yueh B, Priante AVM, Melo RL, Correia LM,

Köhler HF, Toyota J, Kowalski ISG, Kowalski LP. Long-term quality-of-life

evaluation after head and neck cancer treatment in a developing country. Arch

Otolaryngol Head and Neck Surg 2004; 130: 1209-13.

7- Crevenna R, Zettinig G, Keilani M, Posch M, Schmidinger M, Pirich C, Nuhr

M, Wolzt M, Quittan M, Fialka-Moser V, Dudczak R. Quality of life in

patients with non-metastatic differentiated thyroid carcinoma under thyroxine

supplementation therapy. Support Care Cancer 2003; 11: 597-603.

8- Dagan T, Bedrin L, Horowitz Z, Chaushu G, Wolf M, Kronenberg J, Talmi

YP. Quality of life of well-differentiated thyroid carcinoma patients. J

Laryngol Otology 2004; 118: 537-42.

9- Vartanian JG, Carvalho AL, Yueh B, Furia CLB, Toyota J, McDowell JA,

Weymüller Jr WA, Kowalski LP. Brazilian-Portuguese validation of the

University of Washington Quality of Life Questionnaire for patients with head

and neck cancer. Head Neck 2006; 28: 1115-21.

10- Mazzaferri EL. An overview of the management of papillary and follicular

thyroid carcinoma. Thyroid 1999; 9: 421-27.

11- Bilimoria KY, Bentrem DJ, Linn JG, Freel A, et al. Utilization of total

thyroidectomy for papillary thyroid cancer in the United States. Surgery 2007;

142: 906-13.

12- Gonçalves Filho J, Kowalski LP. Postoperative complications of

thyroidectomy for differentiated thyroid carcinoma. Am J Otolaryngol 2004;

25: 225-30.

13- Gonçalves Filho J, Kowalski LP. Surgical complications after thyroid surgery

performed in a cancer hospital. Otolaryngol Head Neck Surg 2005; 132: 490-

94.

14- Bushnell DL, Boles MA, Kaufman GE, Wadas MA, Barnes E. Complications,

sequela and dosimetry of iodine-131 therapy for thyroid carcinoma. J Nucl

Med 1992; 33: 2214-21.

15- Alexander C, Bader JB, Schaefer A, Finke C, Kirsch CM. Intermediate and

long-term side effects of high-dose radioiodine therapy for thyroid carcinoma.

J Nucl Med 1998; 39: 1551-54.

16- Maier H, Bihl H. Effecto of radioactive iodine therapy on parotid gland

function. Acta Otolaryngol 1987; 103: 318-24

17- Botella-Carretero JI, Galán JM, Sancho J, Escabar-Marreale HF. Quality of

life and psycometric functionality in patients with differentiated thyroid

carcinoma. Endocrine-Related Cancer 2003; 10: 601-10.

18- Chow SM, Au KH, Shoy TS, Lee SH, Yeung NY, Leung A, Leung A, Leung

HL, Shek CC, Law SCK. Health-related quality-of-life study in patients with

carcinoma of the thyroid after thyroxine withdraw for whole body scanning.

Laryngoscolpe 2006; 116: 2060-66.

19- Kung S, Rummans TA, Colligan RC, Clark MM, Sloan JA, Novotny PJ,

Huntington JL. Association of optimism-pessimism with quality of life in

patients with head and neck and thyroid carcers. Mayo Clin Proc 2006; 81:

1545-52.

20- Tagay S, Herpertz S, Langkafel M, Erim Y, Bockisch A, Senf W, Görges R.

Health-related quality of life, depression and anxiety in thyroid cancer

patients. Quality of LIfe Reseach 2006; 15: 695-703.

4.1.2 Artigo 2: Late side effects of radioactive iodine therapy on salivary gland

function in patients with thyroid cancer

J.P. Almeida

, A.E. Sanabria

, E.N.P. Lima

, L.P. Kowalski

Department of Head and Neck Surgery and Otorhinolaringology, Hospital A. C.

Camargo, Rua Professor Antonio Prudente, São Paulo, Brazil.

Department of Surgery, Universidad de La Sabana – Fundacion Clinica Abood

Shaio, Diagonal, Bogota, Colombia.

Department of Nuclear Medicine, Hospital A. C. Camargo, Rua Professor Antonio

Prudente, São Paulo, Brazil.

Submetido para

Thyroid 2009

Summary

One hundred eighty two patients were evaluated in a retrospective cohort

study to describe late side effects of Radioiodine Therapy (RIT) on salivary gland

function in patients with well-differentiated thyroid cancer. One hundred six patients

were submitted to total thyroidectomy and adjuvant RIT and 76 underwent only total

thyroidectomy. Assessment of salivary function was performed with salivary gland

scintigraphy (SGS), sialometry and subjective questions to assess the common side

effects of RIT on salivary glands function. Five patients reported recurrent swellings

of the salivary glands after RIT with or without pain, and 28 patients reported taste

disturbance. At univariate analyses RIT had a strong association with decreased

elimination counts at SGS. Age was the only variable associated with unstimulated

salivary flow (USSF) and to stimulated salivary flow (SSF) age and use of

xerostomic drugs were strongly associated with decreased mean values of salivary

flow (p<.001 and p=.001, respectively). Dysphagia complaint was strongly

associated with RIT (p=.002). At multiple logistic regression age was an important

factor associated to salivary gland dysfunction and RIT is strongly associated with

impairment of saliva excretion. These results show that age is an important factor to

salivary gland function, but also show that patients submitted to RIT have more

difficulty in draining saliva, mainly from the parotid glands. This finding suggests

that the mechanism of sialodenitis associated with RIT is more influenced by a ductal

system constriction than significant acinar damage.

Key words: thyroid cancer, radioactive iodine, salivary gland dysfunction, head and

neck cancer.

Introduction

Saliva has several significant roles in maintaining oral function, through the

action of proteins such as amylase, immunoglobulins and lysozymes. It also

lubricates the oral mucosa, allowing proper speaking, swallowing and tasting. Loss

or decrease of salivary production or flow can impair the ability to perform these

functions and is remarkably associated with post-radiation or radioiodine treatment

morbidities (1). In the unstimulated state, about two-thirds of the normal volume of

saliva is produced by submandibular glands. However, depending on the type of

stimuli, the parotid glands can account for about 50% of the volume of saliva (2).

According to Helman et al. (3), salivary glands concentrate iodine,

substituting the Cl

as a substrate for the Na

/Cl

co-transport system. This ability

to concentrate iodine and radioactive iodine makes the salivary glands potential

targets during and after the diagnostic or therapeutic use of these substances (1, 4).

As a consequence, sialadenitis, taste disturbances, xerostomia and an increase in the

number of dental cavities are recognized as short- and long-term effects of

radioiodine therapy (RIT) on salivary glands (1).

The aim of this study is to describe the late side effects of RIT associated with

salivary gland function in patients treated for differentiated thyroid carcinoma

submitted to total thyroidectomy followed or not by adjuvant therapeutic doses of

radioactive iodine.

Patients and Methods

Design

A cross-sectional study of patients with differentiated thyroid cancer (DTC),

who underwent total thyroidectomy associated or not to adjuvant radioiodine therapy

(RIT) from 1997 to 2006 was performed. Patients submitted to prior head and neck

radiation or with symptoms of sicca syndrome were excluded. The study was

approved by the institutional ethics committee and all patients signed an informed

consent form.

The patients were invited to participate in this study on their follow-up

medical consultations. All the patients were under suppressive doses of

levothyroxine and had normal thyroid hormone levels. Only patients from 2 months

to 10 years from treatment end were included, with a median post-treatment time of

24.0 months. The independent variables were age, gender, RIT dose, use of

xerostomic drugs, xerostomia and dysphagia complaints. The dependent variables

were the uptake and elimination percentage of salivary gland scintigraphy and the

unstimulated and stimulated salivary flow of sialometry.

Data about xerostomic drug use were obtained by asking the patient if they

used any antidepressant, antihistaminic or hypotensive drugs.

Sample

Four hundred patients that fulfilled the inclusion criteria were invited to

participate in this study. Of those, 182 patients agreed to participate, 168 patients

completing salivary gland scintigraphy and 179 patients performing sialometry. A

total of 159 (87.5%) were female and 23 (12.6%) were male with the mean age of

49.7 years and the median age of 49 years (range, 23-89 years). One hundred

seventy-seven patients had papillary carcinoma and 5 patients had follicular

carcinoma and all patients were submitted to a total thyroidectomy. One hundred six

(58.2%) patients were submitted to RIT and the median dose was 135mCi (from 30

to 450mCi). Eighty-two patients received doses up to 150 mCi and 26 patients

received doses higher than 150mCi. Seventy-nine (43.4%) patients reported to

occasionally or continuously use xerostomic drugs and 17 (9.5%) patients reported to

feel dry mouth and/or dysphagia. Data are summarized in Table 2.1.

Measures

Patients were categorized in age ≤ or > 45 years, since the age of 45 years is

used as an important prognostic value reference in DTC patients (5).

Many studies have discussed that radioactive iodine effects are dose-

dependent and a recent study of our group showed that doses higher than 150mCi

have more side effects on salivary glands (6, 7). Therefore, we subcategorized the

RIT variable into patients that received up to 150mCi and those that received more

than 150mCi.

Some subjective questions were answered by all patients: (a) “Do you feel

your mouth is dry?”; (b) “For what periods of the day?”; (c) “Do you have difficulty

eating?”; (d) “What kinds of foods?”; (e) “Do you have any difficulty speaking?”; (f)

“Do you have any taste disturbances?”; (g) “What flavors?”; (h) “Do you have any

swelling in the salivary gland regions?”; and (i) “When does it occur?”. These

questions were created to identify the most common complaints related to salivary

gland dysfunction.

Salivary Gland Scintigraphy

Salivary gland scintigraphy (SGS) was performed with a gamma camera (GE

StarCam 4000, GE Medical System, Milwaukee, WI, USA), fitted with a low-energy

high-resolution (LEHR) collimator, energy peak set at 140KeV and 15% window.

Each patient received 10 mCi (370MBq) of

99m

TcO

4 -

, intravenously administrated.

Dynamic images were obtained in 90 seconds (one second/image) with a 128 X 128

matrix in anterior projection. Static images of anterior and lateral projections, with a

256 X 256 matrix, were obtained during 180 seconds per image, before and after

salivary gland stimulation with 500mg ascorbic acid (Cewin®, Sanofi-Synthelabo,

Brazil) orally administrated for five minutes. At the workstation computer, regions of

interest (ROIs) were created on the salivary gland regions and the regional counts

were verified. The uptake rate was calculated to each major salivary gland, bilateral

parotid and bilateral submandibular, as the count percentage of the real dose retained

in each pair of glands. The real dose was 10mCi in counts subtracting the dose in

counts retained in the local of injection and the dose in counts remained in the

syringe. The elimination fraction was calculated as the difference between the count

in each pair of glands pre-stimulus and post-stimulus. This difference was converted

as a percentage of the total uptake. SGS was intended to evaluate the salivary gland

function through the percentage of

99m

TcO

4 -

uptake and elimination.

Sialometry

Sialometry was performed as described by Koseki et al. (8), and whole saliva

was collected in a tube of 15 ml for five minutes and 500mg ascorbic acid (Cewin®,

Sanofi-Synthelabo, Brazil) orally administrated was used to obtain the stimulated

salivary flow. The salivary flow was expressed in ml/min. The normal parameters

were based on data published by Jensen et al. (2), who described cutoffs of

unstimulated salivary flow (USSF) at 0.3 ml/min and stimulated salivary flow (SSF)

at 1.5 ml/min.

Statistical Analysis

For statistical analysis, t-test was employed for univariate analysis, with

multivariate analysis by multiple linear regressions employed to determine the real

independent variables that affected the sialometry and scintigraphy values. For

comparisons, a p-value < 0.05 was considered significant.

Results

Five patients (2.8%) reported at the time of the study recurrent swelling of the

salivary glands after RIT with or without pain. From these five patients, three had

swelling of the salivary glands only while eating and two spontaneously. Most

patients that reported recurrent sialadenitis were unable to give precise information

on the temporal relationship with RIT. Sialadenitis was diagnosed by a swelling in

the region of major salivary glands with or without pain with spontaneous resolution

and without clinical signs of bacterial or viral infection. The diagnosis of sialadenitis

was clinical on the basis of patients’ complaints and physical findings. Twenty-eight

(15.6%) patients reported some kind of persisting taste disturbance and 19 (67.8%)

of those patients had been submitted to RIT.

Univariate Analysis

Only gender showed an association with uptake phase of SGS. Men had a

decreased uptake in all major salivary glands (parotid glands p=.05; submandibular

glands p=.02; all salivary glands p=.03) when compared to women. Other variables

did not show any association. In relation to elimination phase of SGS, as expected,

RIT had a strong association with decreased excretion ability in parotid glands, and

this impairment reflects when elimination was calculated to all glands together

(parotid glands p<.001; all salivary glands p=.002). When doses of radioiodine were

analyzed, there was no influence of doses up to 150mCi or higher than 150mCi in the

uptake or elimination ability. The data are summarized in Table 2.2.

For sialometry, age was the only variable associated with USSF. Patients 45

years of age or younger had a mean value of USS higher than patients older than 45

years of age (p=.02). Other variables did not show association. For SSF, age and the

use of xerostomic drugs were strongly associated with decreased mean values of

salivary flow (p<.001 and p=.001, respectively). Different from salivary gland

scintigraphy, RIT was not associated with altered SSF. Data are summarized in Table

2.3.

The association of RIT with xerostomia complaint was not statistically

significant (p=.63), with 11 patients who reported this complaint had previously been

submitted to RIT and 6 patients had not. For dysphagia complaint, this association

was strongly significant (p=.002). Of those 17 patients with a complaint of

dysphagia, 16 had been submitted to RIT.

Multivariate Analysis

Age was the strongest predictor to parotid gland dysfunction, affecting uptake

and elimination phases of the parotid glands at SGS, USSF and SSF at sialometry.

Gender remains affecting uptake phase of SGS and RIT interferes with the excretion

ability of salivary glands, mainly in parotid glands, verified by elimination phases

and SSF in SGS and sialometry, respectively. The use of xerostomic drugs affected

the SSF at sialometry (Table 2.4).

Discussion

In this study, incidences of sialadenitis and taste disturbance are small as

compared to those published by Alexander et al. (6). Our sialadenitis rate was 2.8%

and taste disturbance was 15.6%, while Alexander et al. (6) published an incidence

of 33% and 27%, respectively. These differences can probably be explained based on

the design of the studies. The data published by Alexander et al. (6) were collected in

a prospective cohort-type study, which has more sensitivity power when subjective

data are collected. In our study, which is retrospective cohort-type, we depend on the

memory of patients and how important those side effects are to them.

As discussed in many studies (9, 10, 11), age is an important factor that

affects salivary gland function. This study reinforced the role of age on salivary

gland function, with patients older than 45 years of age showing lower uptake and

elimination counts at SGS, and lower values to USSF and SSF at sialometry.

Different from all studies published about the influence of gender on salivary

gland function (10, 12), which always report that females had lower salivary gland

function, our study showed lower uptake counts at SGS in men, but no other

alteration in elimination counts or USSF/SSF associated to gender.

As previously reported by other studies (4, 6, 13), salivary glands can present

dysfunction when exposed to radioiodine. Their ability to eliminate

99m

TcO

after

RIT diminishes significantly. The crossing of radioiodine through the Na

/Cl

co-

transport system depends on its correct functioning, and it is known that this system

is affected by radiation during the RIT (3, 14). This excretion impairment can be

associated with ductal system constriction, acute periductal inflammation and

chronic sclerosis induced by radioiodine, since this transport system is mostly

prevalent in the ductal cells (15). Confirming this theory, the results of univariate and

multivariate analysis showed impairment of the elimination phase mainly in parotid

glands and of SSF at sialometry. Possibly because salivary gland damage related to

radioactive iodine is more concentrated in the ductal system, there were no effects on

uptake phase at SGS which can show the

99m

TcO

4 –

in the periductal region.

Furthermore, periductal constriction makes saliva excretion more difficult when the

production of saliva is higher, reflecting in a diminished SSF rate.

It is important to understand that SGS and sialometry are different ways to

verify salivary gland function and both focus in different phases of saliva production.

SGS is able to detect the path some important ions are delivered into the duct system

to compose the whole saliva with water, proteins and other ions. Sialometry is only

able to quantify the volume of whole saliva that can be composed for all components

in normal quantities or not.

Xerostomic drugs were associated with a lower SSF, probably because they

alter the quantity of liquid that will compose the saliva (16). Xerostomia and

dysphagia complaints were not associated with any method to verify salivary gland

function, but dysphagia complaint was strongly associated to RIT. Dysphagia is a

very well recognized side effect of thyroid cancer treatment (17, 18) and recently our

group published new data about patients submitted to doses higher than 150mCi that

had worse scores for swallowing and many other functional domains of the

University of Washington Quality of Life Questionnaire with a significant impact on

the quality of life (7).

Conclusion

This study has some limitations since it is a retrospective cohort-type study.

However, these results reinforce the influence of age on salivary gland function and

the side effects of RIT on saliva excretion suggesting that the mechanism of

sialadenitis associated with RIT is more influenced by an effect on the ductal system

than by significant acinar damage. This saliva excretion impairment can be reflected

clinically as dysphagia, which has an important impact on the quality of life of these

patients. Prospective studies using videofluoroscopy exams to verify different phases

of swallowing will be important to clarify the impact of surgery and doses of RIT on

the swallowing function.

Table 2.1 - Descriptive analyses of dependent variables.

Total N Percent

Age

≤ 45y

>45y

182

110

39.6

60.4

Gender

Male

Female

182

159

12.6

87.4

RIT

Yes

182

106

58.2

41.8

Xerostomic

Drugs

Yes

182

103

43.4

56.6

Xerostomia

Yes

179

162

90.5

9.5

Dysphagia

Yes

179

162

90.5

9.5

RIT – Radioiodine Therapy

Table 2.2 - Univariate analyses associating salivary gland scintigraphy results with dependent variables.

% parotid uptake* % submandibular uptake* % total uptake* % parotid elimination* % submandibular elimination* % total elimination*

Age

≤ 45y

>45y

1.48

1.32

1.67

1.59

3.14

2.90

29.37

28.43

27.74

29.37

28.91

29.52

P Value

.18 .51 .30 .63 .23 .66

Gender

Male

Female

1.08

1.42

1.25

1.67

2.33

3.09

28.76

28.80

27.20

28.93

28.27

29.42

P Value .05 .02 .03

.99 .40 .58

RIT

Yes

1.36

1.40

1.66

1.56

3.02

2.96

24.76

33.52

27.97

29.66

27.37

31.76

P Value

.76 .44 .81 <.001 .22

.002

RIT

≤150mCi

>150mCi

1.41

1.20

1.70

1.51

3.11

2.71

26.14

22.44

28.75

25.46

28.24

24.65

P Value

.36 .42 .38 .28 .12 .11

Xerostomic Drugs

Yes

1.36

1.39

1.63

1.61

2.99

3.00

27.61

29.77

28.61

28.83

28.75

29.72

P Value

.76 .91 .92 .27 .87 .48

Xerostomia

Yes

1.47

1.36

1.70

1.61

3.17

2.97

29.88

28.56

28.70

28.75

29.63

29.20

P Value

.59 .65 .61 .69 .98 .85

Dysphagia

Yes

1.25

1.38

1.55

1.62

2.80

3.00

24.00

29.18

28.58

28.76

27.10

29.47

P Value

.49 .71 .59 .12 .93 .30

*Mean values; RIT – Radioiodine Therapy

Table 2.3 - Univariate analyses associating sialometry results with independent

variables.

USSF* SSF*

Age

≤ 45y

>45y

.54

.40

2.72

2.08

P Value .02 <.0001

Gender

Male

Female

.55

.44

2.51

2.31

P Value

.20 .36

RIT

Yes

.42

.50

2.23

2.47

P Value

.17 .10

RIT

≤150mCi

>150mCi

.42

.41

2.29

2.01

P Value

.87 .25

Xerostomic Drugs

Yes

.40

.49

2.07

2.53

P Value

.12

.001

Xerostomia

Yes

.33

.46

2.36

2.32

P Value

.17 .84

Dysphagia

Yes

.32

.47

2.00

2.35

P Value

.15 .16

*Mean values; USS – Unstimulated Salivary Flow; SSF – Stimulated Salivary Flow; RIT –

Radioiodine Therapy

Table 2.4 - Multiple linear regression with independent variables.

% parotid

uptake*

% submandibular

uptake*

% total

uptake*

% parotid

elimination*

% submandibular

elimination*

% total

elimination*

USSF* SSF*

Age

≤ 45y

>45y

.045

.135

.056

.039

.837

.322

.010

<.001

Gender

Male

Female

.026

.016

.024

.825

.461

.717

.249

.528

RIT

Yes

.817

.357

.719

<.001

.269

.002

.093

.036

Xerostomic

Drugs

Yes

.911

.764

.832

.575

.799

.650

.444

.028

*P Values; USS – Unstimulated Salivary Flow; SSF – Stimulated Salivary Flow; RIT – Radioiodine Therapy.

References

1. Newkirk KA, Ringel MD, Wartofsky L, Burman KD. The role of radioactive

iodine in salivary gland dysfunction. Ear Nose Throat J 2000;

79(6): 460-8.

Jensen SB, Pedersen AM, Reibel J, Nauntofte B. Xerostomia and

hypofunction of the salivary glands in cancer therapy. Supp Care Cancer

2003;

11(4): 207-25.

Helman J, Turner RJ, Fox PC, Baum BJ.

99m

Tc-pertechnetate uptake in parotid

acinar cells by the Na

/ K

/Cl

co-transport system. J Clin Invest 1987; 79(5):

1310-13.

Mandel SJ, Mandel L. Radioactive iodine and the salivary glands. Thyroid

2003;

13(3): 265-71.

Mazzaferri EL. Papillary thyroid carcinoma: factors influencing prognosis and

current therapy. Semin Oncol 1987;

14(3): 315-32.

Alexander C, Bader JB, Schaefer A, Finke C, Kirsch CM. Intermediate and

long-term side effects of high-dose radioiodine therapy for thyroid carcinoma.

J Nucl Med 1998;

39(9): 1551-54.

Almeida JP, Vartanian JG, Kowalski LP. Clinical predictors of quality of life

in patients with initial differentiated thyroid cancer. Arch Otolaryngol Head

Neck Surg 2009;

135(4): 342-46.

Koseki M, Maki Y, Matsukubo T, Ohashi Y, Tsubota K. Salivary flow and its

relationship to oral signs and symptoms in patients with dry eyes. Oral Dis

2004; 10(2):75-80.

De Rossi SS, Slaughter YA. Oral changes in older patients: a clinician’s

guide. Quintessence Int 2007;

38(9): 773-80.

10. Firat F, Cermik TF, Sankaya A, Berkarda S. Effects of gender and age on the

quantitative parameters of [

99m

Tc]pertechnetate salivary gland scintigraphy in

normal subjects. Nucl Med Commun 2006;

27(5): 447-53.

11.

Yeh CK, Johnson DA, Dodds MW. Impact of aging on human salivary

function: a community-based study. Aging (Milano) 1998;

10(5): 421-8.

12.

Inoue H, Ono K, Masuda W, Morimoto Y, Tanaka T, Yokota M, Inenaga K.

Gender difference in unstimulated whole saliva flow rate and salivary gland

sizes. Arch Oral Biol 2006;

51(12): 1055-60.

13.

Caglar M, Tuncel M, Alpar R. Scintigraphic evaluation of salivary gland

dysfunction in patients with thyroid cancer after radioiodine treatment. Clin

Nucl Med 2002;

27(11): 767-71.

14.

Nahlieli O, Nazarian Y. Sialadenitis following radiodine therapy – a new

diagnostic and treatment modality. Oral Dis 2006;

12(5): 476-79.

15.

Jhiang SM, Cho JY, Ryu KY, DeYoung BR, Smanik PA, McGaughy VR et

al. An immunohistochemical study of sodium/iodine symporter in human

thyroid tissues and salivary gland tissues. Endocrinology 1998;

139(10):

4416-19.

16.

Almeida PV, Grégio AM, Brancher JA, Ignacio SA, Machado MA, de Lima

AA, et al. Effects of antidepressants and benzodiazepines on stimulated

salivary flow rate and biochemistry composition of the saliva. Oral Surg Oral

Med Oral Pathol Oral Radiol Endod 2008;

106(1): 58-65.

17.

Lombardi CP, Raffaelli M, D’Alatri L, Marchese MR, Rigante M, Paludetti G

et al. Voice and swallowing changes after thyroidectomy in patients without

inferior laryngeal nerve injuries. Surgery 2006;

140(6): 1026-32.

18. Nguyen NP, Smith HJ, Sallah S. Evaluation and management of swallowing

dysfunction following chemoradiation for head and neck cancer. Curr Opin

Otolaryngol Head and Neck Surg 2007;

15(2):130-3.

4.1.3 Artigo 3: The use of pilocarpine to treat xerostomia in patients submitted to

radioactive iodine therapy: a pilot study.

Almeida JP, DDS, MS; Kowalski LP, MD, PhD

Department of Head and Neck Surgery and Otorhinolaryngology, Hospital A.C.

Camargo

Submetido para

Oral Diseases 2009

Abstract

Objectives: Report the experience with use of pilocarpine on the treatment of

xerostomia in thyroid cancer patients submitted to adjuvant radioactive iodine

therapy (RIT). Subjects and methods: Five patients meeting the inclusion criteria

received 5mg of pilocarpine, 3 times per day, for one week. Side effects of the drug

and subjective response to xerostomia complaints after treatment were evaluated.

Results: Sudoresis was the most frequent side effect of pilocarpine use, followed by

fatigue and headache. Two patients reported relief of xerostomia using pilocarpine,

but only one patient was able to tolerate the side effects. Conclusions: Pilocarpine

seems to relieve xerostomia complaints in thyroid cancer patients since it is able to

stimulate salivary flow, but the observed side effects made the patients refuse long-

term therapy continuation.

Keywords: xerostomia; pilocarpine; thyroid cancer; radioactive iodine therapy

Introduction

The saliva plays an integral part in maintaining oral functions and the loss or

decrease of salivary flow or production can impair the ability to perform its functions

and is associated with increased morbidity, thus impacting the patient’s quality of

life. The ability to concentrate iodine on the salivary glands makes them potential

targets during and after radioiodine therapy (RIT) (Newkirk et al. 2000).

Serious acute complications with RIT are extremely rare. However,

intermediate and long-term side effects are well described in the literature as

sialodenitis, transient loss of taste, xerostomia and cavities (Bushnell et al. 1992,

Alexander 1998, Newkirk et al. 2000).

Xerostomia is the sensation of dry mouth reported by the patient (Jensen et al.

2003). Xerostomia can be caused by many factors as local and systemic diseases,

medications, radiation, and chemotherapy. Alexander et al. (1998) and Caglar et al.

(2002) reported rates of xerostomia associated to RIT as high as 42.9% and 54%,

respectively, normally 1 year after the therapy. Our studies have shown that 11.2% of

the patients submitted to RIT have persistent xerostomia complaints (during the

entire day) (Almeida et al. 2009).

Treatment of xerostomia is difficult and involves symptomatic relief by the

administration of sour-tasting sugarless candies, sips of water, saliva substitutes and

drug treatment with the use of sialogogues. Pilocarpine is a parasympathomimetic

agent with mild β-adrenergic properties that stimulate cholinergic receptors on the

surfaces of the exocrine glands, causing a reduction of the symptoms of xerostomia.

Reported serious adverse events are rare with pilocarpine, but side effects as

sweating, flushing and urinary frequency are common, with typically mild or

moderate intensity for a relatively short duration (Fox et al. 2004).

The aim of this pilot study is to describe the feasibility and efficacy of

pilocarpine as a treatment of xerostomia in patients submitted to RIT.

Patients and methods

This report is part of a large study that invited 400 patients treated for well-

differentiated thyroid cancer, submitted or not to RIT from 1997 to 2006. Of those,

184 patients accepted to participate in the study and signed a consent form. One

hundred eighty patients had papillary carcinoma and only four had follicular

carcinoma. The mean age of the patients was 49.9 years and the median age was 49

years (25 - 89y). One hundred eight (58.7%) patients were submitted to RIT and 76

(41.3%) were not. Seventy-eight (42.4%) patients used some kind of xerostomic

drug. All patients were submitted to sialometry and salivary gland scintigraphy.

The criteria to enter the pilocarpina protocol was: patients submitted to RIT

presenting at the same time with xerostomia complaints, abnormal values at

sialometry (unstimulated ≤ 0.3 ml/min; stimulated ≤ 1.5 ml/min) (Jensen 2002) and

visual dysfunction at the salivary gland scintigraphy, and without clinical contra-

indications to pilocarpine such as asthma, hypertension, cardiac diseases and close-

angle glaucoma. Blood pressure was verified before the beginning of pilocarpine

treatment and the treatment consisted of 5 mg of pilocarpine 3 times per day as

recommended by the literature (Fox 2004), mainly before meals and at night, during

1 week. The patients filled out a control questionnaire about side effects and reported

all symptoms during seven days.

Results

Of 108 patients submitted to adjuvant RIT, 65.4% (70 patients) reported

xerostomia at least one period of the day and 11.2% (12 patients) all the time. Of

these 70 patients, only nine patients met the criteria for pilocarpine treatment. The

mean age of the patients was 52.1 years and the median age was 56 years (36–65y).

The mean dose received of radioactive iodine was 183.3 mCi and the median dose

was 150 mCi (100–450 mCi). Of these nine patients, four patients were not included

in the study. One patient did not accepted to participate in the study, and three

patients had arterial hypertension. The data of treated patients are summarized in

table 3.1.

Table 3.1 - Data of five patients who completed one week of treatment with

pilocarpine

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5

Age

38 56 57 58 36

RIT (mCi)

200 100 150 250 450

USSF (ml/min)

0.02 0.24 0.30 0.24 0.30

SSF (ml/min)

0.42 1.38 1.10 1.16 1.50

Blood pressure (mmHg)

140 x 80 120 x 80 140 x 90 120 x 80 110 x 60

Sudoresis

9 9 9 9

Urinary frequency

9 9

Lacrimation

9 9

Shivering

9 9

Fatigue

9 9 9

Dizziness

9 9

Nausea

9 9

Headache

9 9 9

High blood pressure

Taquicardia

End result

NT T NT T NT

NT – No Tolerance to treatment due to side effects of pilocarpine; T – Tolerance to treatment and the

patient was able to use pilocarpine for one week and had relief of xerostomia symptoms.

The most frequent side effect reported by the patients was sudoresis, affecting

4 out of 5 patients. Fatigue and headache were reported by 3 out of the 5 patients.

Increase of urinary frequency, lacrimation, shivering, dizziness and nausea had the

frequency of 2 in 5 patients. Alterations of blood pressure and taquicardia were

reported by the same single patient. Evaluating the relief of xerostomia after

pilocarpine use, two patients reported improvement of dry mouth sensation, but one

with many side effects considered the use unacceptable.

Discussion

As opposite to external radiation, Iodine-131 therapy does not completely

destroy salivary gland ability to secrete saliva, adequately preserving functional

parenchyma to respond upon stimulus. Xerostomia is reported by 11 to 54% of

patients submitted to RIT (Alexander et al. 1998, Caglar et al. 2002, Almeida et al.

2009). As differentiated thyroid cancer has good prognosis, reduction of RIT long-

term oral side effects is essential in maintaining the patient’s quality of life.

Contrary to external radiation therapy, which has many studies showing the

efficacy of pilocarpine on salivary gland stimulus (LeVeque et al. 1993, Hamlar et al.

1996, Zimmerman et al. 1997, Horiot et al. 2000, Leek e Albertsson 2002, Haddad e

Karimi 2002, Gorsky et al. 2004, Mosqueda-Taylor et al. 2004), the literature lacks

studies analyzing the efficacy of pilocarpine to relieve xerostomia symptoms

associated to RIT. Silberstein (2008) published results of the use of pilocarpine in a

single-blind controlled study with 60 patients for one week after RIT trying to

prevent sialadenitis associated to Iodine-131. This study showed that pilocarpine also

did not reduce the occurrence of radiation sialadenitis. These results confirm data

published by Alexander et al. ten years before, that did not observe significant

difference between the patients who received pilocarpine during RIT and those who

did not.

Aiming to show another use of pilocarpine, Aframian et al. (2006) published

a study showing the efficacy of a single-dose of pilocarpine on the entire

unstimulated and stimulated salivary flow in five patients suffering from thyroid

cancer treated with adjuvant RIT at least 3 months prior to study. The results showed

significant elevation of unstimulated and stimulated saliva flow rate in four patients

without significant alteration of systolic and diastolic blood pressure, pulse rate and

body temperature.

Until the moment, no study in the literature uses pilocarpine for long-term

treatment of xerostomia associated to RIT and evaluates the tolerability of the drug.

The present study shows results that are not favorable to the use of pilocarpine as a

routine treatment. The side effects with 3 doses per day for one week were not well

tolerated by thyroid cancer patients and the use of this drug could not be further

recommended since the benefits did not offset the side effects.

References

1. Aframian DJ, Helcer M, Livni D, Markitziu A. Pilocarpine for the treatment

of sakuvary glands‘ impairment caused by radioiodine therapy for thyroid

cancer.

Oral Diseases 2006; 12: 297-300.

Alexander C, Bader JB, Schaefer A, Finke C, Kirsch CM. Intermediate and

long-term side effects of high-dose radioiodine therapy for thyroid carcinoma.

J Nucl Med 1998; 39: 1551-54.

3. Bushnell DL, Boles MA, Kaufman GE, Wadas MA, Barnes E.

Complications, sequela and dosimetry of iodine-131 therapu for thyroid

carcinoma.

J Nucl Med 1992; 33: 2214-21.

Caglar M, Tuncel M, Alpar R. Scintigraphic evaluation of salivary gland

dysfunction in patients with thyroid cancer after radioiodine treatment.

Clin

Nucl Med 2002; 27: 767-71.

Fox PC. Salivary enhancement therapies. Caries Res 2004; 38: 241-6.

Gosrky M, Epstein JB, Parry J, Epstein MS, Le ND, Silverman S Jr. The

efficacy of pilocarpine in cancer patients with hyposalivation following

radiation therapy.

Oral Surg Oral Med Oral Pathol 2004; 97: 190-95.

Haddad P, Karimi M. A randomized, double-blind, placebo-controlled trial of

concomitant pilocarpine with head and neck irradiation for prevention of

radiation-induced xerostomia.

Radiot Oncol 2002; 64: 29-32.

Hamlar DD, Schuller DE, Gahbauer RA, et al. Determination of the efficacy

of topical oral pilocarpine for postradiation xerostomia in patients with head

and neck carcinoma.

Laryngosc 1996; 106: 972-76.

Horiot JC, Lipinski F, Schraub S, et al. Post-radiation sever xerostomia

relieved by pilocarpine: a prospective French cooperative study.

Radiot

Oncol

2000; 55: 233-39.

10.

Jensen SB, Pedersen AM, Reibel J, Nauntofte B. Xerostomia and

hypofunction of the salivary glands in cancer therapy.

Supp Care Cancer

2003; 11: 207-25.

11.

Leek H, Albertsson M. Pilocarpine treatment of xerostomia in head and neck

patients.

Micron 2002; 33: 153-55.

12. LeVeque FG, Montgomery M, Potter D, et al. A multicenter, randomized,

double-blind, placebo-controlled, dose-titration study of oral pilocarpine for

treatment of radiation-induced xerostomia in head and neck cancer patients.

Clin Oncology 1993; 11: 1124-31.

13.

Mosqueda-Taylor A, Ortiz KL, Camacho MEI, Franco MAD, Muñoz AMC.

Efecto del clorhidrato de pilocarpina como estimulante de la producción

salival en pacientes sometidos a radioterapia de cabeza y cuello.

Med Oral

2004; 9: 204-11.

14.

Newkirk KA, Ringel MD, Wartofsky L, Burman KD. The role of radioactive

iodine in salivary gland dysfunction.

ENT J 2000; 79: 460-68.

15.

Silberstein EB. Reducing the incidence of

131

I-induced sialadenitis: the role of

pilocarpine.

J Nucl Med 2008; 49: 546-9.

16.

Zimmerman RP, Mark RJ, Tran LM, Juillard GF. Concomitant pilocarpine

during head and neck irradiation is associated with decreased posttreatment

xerostomia.

Int J Radiation Oncol Biol Phys 1997; 37: 571-75.

4.2 ESTUDO II

Os resultados do estudo II estão descritos no artigo.

4.2.1 Artigo 4: Amifostine protection of radioiodine side effects on salivary

glands: a prospective, randomized and double-blind study

Juliana P Almeida

, Dionísio N Viviani

, Renato Barra

, Marília Maroni

, Euclides T

Rocha

, Eduardo Tinois

2,3

, Milene M Foschini

, André L Carvalho

, Luiz Paulo

Kowalski

Department of Head and Neck Surgery and Othorinolaryngology, Hospital A. C.

Camargo

Department of Nuclear Medicine, Barretos Cancer Hospital

Department of Physics in Nuclear Medicine, AmorimTinois Graphic Computer

Department of Epidemiology and Statistics, Research Support Center, Barretos

Cancer Hospital

Department of Nuclear Medicine, Hospital Samaritano de São Paulo

Thanks to Stela Verzinhasse for her contribution with statistical analysis.

Submetido para

Journal of Clinical Oncology 2009

Abstract

Purpose

: Radioactive iodine therapy (RIT) has many salivary glands effects and

amifostine has been suggested to protect salivary glands during this therapy. This

randomized, double-blind study aims to describe the protection effects of amifostine

on salivary glands in patients submitted to RIT as adjuvant treatment to well-

differentiated thyroid carcinomas. Patients and methods

: thirty patients were

randomized to receive 200 mg/m

of subcutaneous amifostine or saline solution as

placebo before to receive therapeutic dose of radioactive iodine. Patients were

evaluated with salivary gland scintigraphy, sialometry and subjective questions

before and 3 months after RIT to investigate the efficacy of amifostine to protect

salivary glands. Results

: There were no differences between groups in all variables

before treatment. During RIT, amifostine neither decreased the incidence of

sialodenitis related to

131

I, nor the pain related to sialodenitis or the taste disturbance

related to

131

I, but it was able to decrease the mean time of sialodenitis related to

131

from 6.27 days in placebo to 3.5 days in amifostine group (P = .02). Three months

after RIT there were no differences of parotid/submandibular uptake pre-stimulus

between groups (amifostine P = .86; placebo P = .86). Values of parotid constant of

excretion of -1.69%/min versus -5.03%/min in amifostine and placebo groups,

respectively, show a diminished excretion function of parotid in both groups 3

months after RIT, higher in placebo but with no significant difference (P = .86). The

values of submandibular constant of excretion of 1.51 %/min versus 1.99 %/min (P =

.91) in amifostine and placebo groups, respectively, show that submandibular glands

maintain the excretion function better than parotid glands after RIT. Conclusion

: 200

mg/m

of subcutaneous amifostine was not able to protect salivary glands of acute

side effects of RIT. More studies are needed to determine the safe and effective dose

of amisfotine in thyroid cancer patients.

Key words: radioactive iodine, sialodenitis, side effects, amifostine, slivary glands

Introduction

Salivary glands concentrate iodine, substituting the Cl

as a substrate for the

/Cl

co-transport system.

This ability to concentrate iodine and radioactive

iodine makes the salivary glands potential targets during and after the diagnostic or

therapeutic use of these substances.

2-3

As a consequence, sialadenitis, taste

disturbances, xerostomia and an increase in the number of dental caries are

recognized as short- and long-term side effects of radioiodine therapy (RIT) on

salivary glands.

2-4

Amifostine is a thiophosphate that has been suggested to play a salivary gland

protection against radiation and chemotherapy.

It has been used in head and neck

radiation with controversial results in the literature,

6-7

but with thyroid cancer

patients submitted to radioiodine therapy (RIT) the first data were presented by

Bohuslavizki et al

in 1998 and subsequently by Kim et al

in 2008. The study

published by Bohuslavizki et al

is a double-blind and placebo-controlled study, with

50 patients included, that showed reduction of parenchymal damage in salivary

glands caused by RIT with the use of amifostine. The study published by Kim et al

is a non-randomized study, with 80 patients that did not show cytoprotective effects

of amifostine for differentiated thyroid cancer patients treated with

131

I. The side

effects of RIT as sialodenitis, xerostomia and taste disturbance are well discussed in

the literature,

2-4

and the impact of these side effects on quality of life of these patients

has been showed recently.

Effective ways to protect the patients to the side effects

of RIT must be investigated to improve the long-term quality of life of these patients.

The aim of this study is to describe the protection effects of amifostine on

salivary glands in patients submitted to RIT as adjuvant treatment to well-

differentiated thyroid carcinomas.

Patients and methods

Design

This is a prospective, randomized and double-blind study of 30 patients, who

underwent total thyroidectomy and were submitted to adjuvant radioiodine therapy

(RIT). Patients submitted to prior RIT, head and neck external radiation, with

symptoms of Sicca Syndrome or any contraindication to amifostine use

(hypersensibility to aminothyol, low blood pressure, dehydratation, kidney or liver

insufficiency, age over 70 years, pregnancy or lactation period) were excluded. The

study was approved by the institutional ethics committee and all patients signed an

informed consent form. This study was also registrated at Brazilian National

Information System on Research Ethics under the number 1342.0.022.000-06.

Initially, the patients randomized to amifostine group (AG) received 500

mg/m

(Ethyol®, Shering Plough Brazil) intravenously and those patients

randomized to placebo group (PG) received 1 ml of physiologic saline solution. After

inclusion of 4 patients, due to reasons related bellow, dose of amifostine has been

changed to 200 mg/m

administrated subcutaneously. Blood pressure was verified

before and 15 minutes after administration of solutions and just after radioiodine was

administrated. In this initial protocol were included 4 patients, but the last 2 included

patients presented serious side effects after infusion. One patient had blood pressure

30 x 60 mmHg and it was very difficult to recovery the blood pressure, and the last

patient had vomiting for 3 consecutive hours with no response to antiemetic

medications. After these events we broke the double-blind to report to ethics

committee and confirmed that the first two patients had been randomized to placebo

group and the last two patients had been randomized to amifostine group. After these

serious side effects we changed the protocol to go on the study and the dose of

amifostine was reduced to 200 mg/m

administrated subcutaneously.

The independent variables were age, gender, RIT dose, use of xerostomic

drugs, xerostomia, taste disturbance and dysphagia complaints. The dependent

variables were the uptake and constant of elimination of salivary glands scintigraphy

and the unstimulated and stimulated salivary flow sialometry. Data about use of

xerostomic drugs were obtained asking to the patient if she/he used some

antidepressant, antihistaminic or hypotensive drugs.

Sample

The first four patients initially included in the study were 3 women and 1

man, with a mean age of 45.5 years, but these patients were not included in the final

analysis, since these patients did not complete the protocol.

With the second protocol, the study was concluded with 30 patients, but one

patient did not complete the evaluation of 3 months after RIT. From 29 patients that

completed the study, 11 were randomized to amifostine group (AG) and 18 were

randomized to placebo group (PG). The mean age was 36.2 years in AG (median 36

years, ranging from 18 to 61 years of age) and in PG the mean age was 38.2 years

(median 38.5 years, ranging from 20 to 59 years of age). There was no difference

between the groups in relation to age (P = .54).

A total of 23 patients were female (10 patients in AG and 13 in PG) and 6

patients were male (1 patient in AG and 5 in PG). Nine patients of AG had papillary

carcinoma, one patient had follicular carcinoma and one patient had Hurtle cell

carcinoma. In PG, 16 patients had papillary carcinoma, one follicular carcinoma and

one Hurtle cell carcinoma. The majority of patients had tumors in clinical stage I (11

in AG and 15 in PG). Only 2 patients of PG had tumors in clinical stage III (Table

4.1).

RIT was performed with patients receiving orientations to use lemon during

the hospital admission and dimenidrinate 100 mg 6/6 hours (Dramin®, Nycomed

Pharma, Brazil) if necessary. The mean dose received at RIT in AG was 6.05 GBq

and in PG was 6.68 GBq. The median dose in AG was 5.55 GBq (3.70 - 7.40 GBq)

and in PG was 6.47 GBq (3.70 - 14.80 GBq), with no significant difference between

the groups (P = .52).

Measures

Subjective Questionnaire

Some subjective questions were answered by all patients before and 3 months

after RIT: 1- Do you feel your mouth to be dry? 2- For what periods of the day? 3-

Do you have difficulty eating? 4- What kinds of foods? 5- Do you have any difficulty

speaking? 6- Do you have taste disturbances? 7- What flavors? 8- Do you have any

swelling in salivary gland regions? 9- When does it occur? These questions were

created to identify the most common complaints related to salivary gland

dysfunction.

Salivary Gland Scintigraphy

The protocols used for acquisition and processing were similar for all of the

subjects. After venous puncture in a superficial vein of the arm, dynamic salivary

gland scintigraphy (SGS) was obtained immediately after intravenous administration

of 370MBq of

99m

Tc-pertechnetate, in a dual time point protocol before and 3 months

after RIT. Blood flow was measured and after that the uptake and excretion were

verified. The acquisition of images was performed in a dual head gamma camera

equipped with low-energey and high resolution collimators (Millennium VG,

General Eletric Medical System). It was used a standard protocol with image

acquisition every 3 seconds in the first minute, and every 30 seconds for 29 minutes,

with a matrix of 128x128 pixels and magnification of 1.5 times. Furthermore, the

stimulation with lemon juice was carried out at 20 minutes into the study with the

purpose to cause salivary secretion.

At the workstation computer, regions of interest (ROIs) were drawn by hand

on the salivary glands (parotid and submandibular salivary glands). As a measure of

salivary gland function, the uptake of

99m

Tc-pertechnetate was calculated as a percent

of the activity injected. Other variable was determined, the Constant of Excretion. It

is the excretion fraction in relation to an unit of time and it is measured using Method

of Least Square with exponential adjust (the constant is the coefficient of exponent)

to points between the maximum (immediately before stimulation) and minimum (the

minimum activity immediately after the stimulation) in the ROI and was expressed

as the elimination percentage per minute (%/min). This variable provides information

about the speed of the excretion.

Sialometry

Sialometry was performed as described by Koseki et al,

and whole saliva

was collected in a tube of 15 ml along five minutes after oral administration of

500mg of ascorbic acid (Cewin®, Sanofi-Synthelabo, Brazil) in order to obtain the

salivary flow stimulation. The salivary flow was expressed in ml/min. The normal

parameters were based on data published by Jensen et al,

who described cutoffs of

unstimulated salivary flow (USSF) at 0.3 ml/min and stimulated salivary flow (SSF)

at 1.5 ml/min.

Statistical Analyses

For statistical analysis Fisher’s Test was used to categorical variables and

Mann-Whitney test was used to continuous variables, since the distribution of same

variables was not normal. For comparisons, a P < .05 was considered statistically

significant.

Results

The clinical characteristics, salivary flow by sialometry and clinical

complaints pre-treatment were the same to both groups. The table 4.1 shows the

distribution of gender, clinical stage, use of xerostomic drugs, stimulated and

unstimulated sialometry and clinical complaints associated to salivary glands

function.

The salivary glands function pre-treatment, verified by salivary glands

scintigraphy, was the same to both groups (Table 4.2). The mean percentage of

parotid/submandibular uptake pre-stimulus of injected dose was 0.71/0.42 and

0.68/0.39 to AG and PG, respectively, and there was no difference between these

uptakes (P = .47; P = .44). To better visualize the salivary glands function, the

constant of excretion was calculated and gives how much percent the glands are able

to eliminate in a period of time as %/min. The parotid/submandibular constant of

excretion pre-treatment were 30.35/6.85 and 26.09/7.58 in AG and PG, respectively,

with no differences between these values (P = .65 to both pair of glands). See

detailed date at table 4.2.

About the acute side effects of

131

I on salivary glands during RIT, amifostine

neither decreased the incidence of sialodenitis related to

131

I, nor the pain related to

sialodenitis or the taste disturbance related to

131

I (Table 4.3). However, the

amifostine was able to decrease the mean time of sialodenitis related to

131

I from 6.27

days in PG to 3.5 days in AG (P = .02). To obtain these results an outlier patient in

AG that persisted with sialodenitis over 90 days after RIT was excluded of the

analysis (Table 4.4).

Although we had some serious problems, as very low blood pressure and

vomiting for 3 hours with amifostine administrated intravenously, with the

subcutaneous via we did not have any side effect associated with the drug

administration. The blood pressure was stable to all patients. Pre-infusion, the

median systolic pressure was 120 mmHg (90-140 mmHg) and 110 mmHg (100-140

mmHg), and diastolic pressure was 80mmHg (70-100 mmHg) and 70 mmHg (60-

100 mmHg) in AG and PG, respectively. After infusion, the median systolic pressure

was 110 mmHg (100-150 mmHg) and 110 mmHg (90-140 mmHg) and the diastolic

pressure was 80 mmHg (60-100 mmHg) and 70 mmHg (60-80 mmHg) in AG and

PG, respectively. There was no difference between the groups. See data in Table 4.5.

To evaluate the amifostine protection of salivary glands against the

deleterious effects of

131

I were calculated the differences between uptake pre- and

post-stimulus post- and pre-treatment and the differences between constant of

excretion post- and pre-treatment. The differences of parotid/submandibular uptake

pre-stimulus were -0.05/-0.04 and -0.10/-0.03 to AG and PG (P = .86; P = .86,

respectively) and the differences of parotid/submandibular uptake post-stimulus were

-0.05/-0.03 and -0.05/-0.02 to AG and PG (P = .82; P = .56, respectively) showing a

reduced capacity to uptake and eliminate but with no statistical difference between

groups. When we compared the constants of excretion, the results are the same with

no differences between the groups. Values of parotid constant of excretion of -

1.69%/min versus -5.03%/min in AG and PG, respectively, show a diminished

excretion function of parotid in both groups 3 months after RIT, higher in PG but

with no significant difference (P = .86). The values of submandibular constant of

excretion of 1.51 %/min versus 1.99 %/min (P = .91) in AG and PG, respectively,

show that submandibular glands maintain the excretion function better than parotid

glands after RIT (Table 4.5).

Discussion

Although a series of studies of Bohuslavizki et al

8,13-14

have shown the

feasibility of amifostine to protect salivary glands in patients submitted to RIT, Kim

et al

could not confirm this find. As Kim et al

in our study, with the methodology

used, we were unable to show the efficacy of amifostine to prevent in a short time the

side effects of RIT on salivary glands.

The first point that must be discussed is the difficulty that we had to use

amifostine intravenously in patients withdraw thyroid hormone. It is reported in the

literature many side effects associated to intravenous administration of amifostine,

but all references report non-thyroid cancer patients. It is important because these

patients normally are withdrawing thyroid hormones to be submitted to RIT and the

reaction of these patients to amifostine had not been fully discussed in the literature

until this moment. Although the two published studies using amifostine with thyroid

cancer patients did not report serious side effects, we had the misfortune of two first

patients included in the intravenous protocol presented serious side effects to

amifostine, what made impracticable going on with that protocol.

The thyroid hormones play an important activity to control some essential

functions as control of metabolic rate, cardiovascular system and blood pressure

regulation.

16-17

Triiodothyronine (T3) affects transcription of many cardiac genes,

including α- and β-myosin heavy chain, which comprise the thick filament of the

contractile unit, the β1-adrenergic receptor, sarcoplasmic reticulum calcium ATPase

(SERCA2), and its regulator, phospholamban, which regulates calcium reuptake into

the sarcoplasmic reticulum and thyroid receptors α1 (TRα1). Alterations in the

relative amounts of these calcium-cycling proteins and the state of phosporylation of

the inhibitor phospholamban might account for changes in diastolic function.

Although patients with hypothyroidism are under higher risk to develop systemic

hypertension due to a peripheral vasoconstriction, when these patients have an abrupt

decrease in the blood pressure, the heart is not able to compensate this change, since

T3 regulates the expression of many cardiac genes responsible for the cardiac

functions, mainly phospholamban which is responsible for the relax phase of cardiac

cells.

In this context, these patients can also be in a greater risk to develop lung

edema with the infusion of a high quantity of physiologic saline solution to recovery

the blood pressure.

Previous studies of our group

10,18

showed that the deleterious effects of RIT

on salivary glands are concentrated in an impairment of salivary glands, mainly

parotid glands, to eliminate saliva and not to produce it, and it impacts in a mean

time of two years after RIT in the quality of life of these patients by interfering with

swallowing function. In this study, we were unable to show the efficacy of

amifostine to reduce side effects of RIT on salivary glands function. Bohuslavizki et

al,

in a prospective, randomized and double-blind study with 50 patients included,

showed the efficacy of amifostine to reduce parenchymal damage in salivary glands

caused by RIT, maintaining a better uptake function. The point is that salivary glands

damage induced by RIT, in middle and long-term, is more serious in excretion phase,

probably due to a periductal constriction by inflammatory process induced by

131

Kim et al.

in a non-randomized study, but analyzing 42 patients treated with

amifostine and 38 patients treated with placebo were unable to show the

cytoprotective effects of amifostine on salivary glands to RIT.

The only favorable find in our study was the capacity of amifostine to reduce

the number of days that patients had symptomatic sialodenitis, but amifostine was

not able to reduce the pain associated to it. In our view this minor benefit does not

justify the risks and the cost using this drug.

Before to conclude that amifostine is not effective to protect salivary glands

of RIT effects more studies are needed to find a safe via of administration,

considering the status withdraw thyroid hormone of these patients, and the more

effective dose. Moreover, it is important to take into consideration, before final

conclusions, the possibility of middle and long-term protective effects related to the

use of amifostine. As the impact of RIT is detected normally up to two years after the

therapy, it is important to follow these patients and evaluate the capacity of

amifostine to prevent late side effects of RIT on salivary glands function.

Table 4.1 - Description of clinical variables of both groups pre-treatment.

Variable

Category

Amifostine

n (%)

Placebo

n (%)

P value

Sialodenitis

Yes

1 (9.1)

10 (90.9)

7 (38.9)

11 (61.1)

.11

Pain

Yes

7 (63.6)

4 (36.4)

10 (55.6)

8 (44.4)

.72

Taste disturbance

Yes

5 (45.5)

6 (54.4)

11 (61.1)

7 (38.9)

.41

Total

11 (100) 18 (100)

Table 4.4 - Amifostine and sialodenitis during RIT.

* Two patients of amifostine group were excluded of this analysis.

One outlier patient who persisted with sialodenitis over 90 days after RIT and one patient that had

missing data about number of days with sialodenitis.

Table 4.5 - Differences between post- and pre-treatment values.

Variable Amifostine

mean (sd)

Placebo

mean (sd)

P value

Pre-stimulus parotid difference *

-0.05 (0.27) -0.10 (0.30) .86

Pre-stimulus submandibular difference *

-0.04 (0.20) -0.03 (0.17) .86

Post-stimulus parotid differece*

-0.05 (0.26) -0.05 (0.18) .82

Post-stimulus submandibular differece *

-0.03 (0.18) -0.02 (0.12) .56

Parotid ejection flow difference**

-1.69 (19.86) -5.03 (24.19) .86

Submandibular ejection flow difference **

1.52 (11.51) 1.99 (13.49) .91

Systolic pressure pre-infusion***

115.0 (17.73) 113.3 (13.45) .64

Diastolic pressure pre-infusion***

81.2 (12.46) 74.0 (9.10) .13

Systolic pressure post-infusion***

113.7 (15.98) 110.0 (13.09) .69

Diastolic pressure post-infusion***

76.2 (13.02) 74.0 (6.32) .65

*Data in percent of the activity injected; ** Data in %/min; ***Data in mmHg.

Number of days with sialodenitis

during RIT

P value

Amifostine*

Mean (sd)

Median (min-max)

3.5 (2.20)

2.5 (2-7)

Placebo

Mean (sd)

Median (min-max)

6.27 (2.15)

7 (2-10)

.02

References

1. Helman J, Turner RJ, Fox PC, et al:

99m

Tc-pertechnetate uptake in parotid

acinar cells by the Na

/ K

/Cl

co-transport system. J Clin Invest 79: 1310-

13, 1987.

Newkirk KA, Ringel MD, Wartofsky L, et al: The role of radioactive iodine in

salivary gland dysfunction. ENT J 79: 460-68, 2000.

Mandel SJ, Mandel L: Radioactive iodine and the salivary glands. Thyroid 13:

265-71, 2003.

Alexander C, Bader JB, Schaefer A, et al: Intermediate and long-term side

effects of high-dose radioiodine therapy for thyroid carcinoma. J Nucl Med

39: 1551-54, 1998.

Bardet E, Martin L, Calais G, et al: Preliminary data of the GORTEC 2000-02

phase III trial comparing intravenous and subcutaneous administration of

amifostine for head and neck tumors treated by external radiotherapy. Semin

Oncol 29: 57-60, 2002.

Brizel DM, Wasserman TH, Henke M, et al: Phase III randomized trial of

amifostine as a radioprotector in head and neck cancer. J Clin Oncol 18: 3339-

45, 2000.

Antonadou D, Pepelassi M, Synodinou M, et al: Prophylatic use of amifostine

to prevent radiochemotherapy-induced mucositis and xerostomia in head and

neck cancer. Int J Radiation Oncology Biol Phys 52: 739-47, 2002.

Bohuslavizki KH, Klutmann S, Brenner W, et al: Salivary gland protection by

amifostine in high-dose radioiodine treatment: results of a double-blind

placebo-controlled study. J Clin Oncol 16: 3542-49, 1998.

9. Kim SJ, Choi HY, Kim IJ, et al: Limited cytoprotective effects of amifostine

in high-dose radioactive iodine 131-treated well-differentiated thyroid cancer

patients: analysis of quantitative salivary scan. Thyroid 18: 325-31, 2008.

10.

Almeida JP, Vartanian JG, Kowalski LP: Clinical predictors of quality of life

in patients with initial differentiated thyroid cancer. Arch Otolaryngol Head

Neck Surg 135: 342-46, 2009.

11.

Koseki M, Maki Y, Matsukubo T, et al: Salivary flow and its relationship to

oral signs and symptoms in patients with dry eyes. Oral Dis 10:75-80, 2004.

12.

Jensen SB, Pedersen AM, Reibel J, et al: Xerostomia and hypofunction of the

salivary glands in cancer therapy. Supp Care Cancer 11: 207-25, 2003.

13.

Bohuslavizki KH, Brenner W, KlutmannS, et al: Radioprotection of salivary

glands by amifostine in high-dose radioiodine therapy. J Nucl Med 39: 1237-

42, 1998.

14.

Bohuslavizki KH, Klutmann S, Jenicke L, et al: Radioprotection of salivary

glands by S-2-(3-aminopropylamino)-ethylphosphorothioic (amifostine)

obtained in a rabbit animal model. Int J Radiation Oncol Biol Phys 45: 181-

86, 1999.

15.

Hensley ML, Hagerty KL, Kewalramani T, et al: American Society of Clinical

Oncology 2008 clinical practice guideline update: use of chemotherapy and

radiation therapy protectans. J Clin Oncol 27: 127-45, 2009.

16.

Danzi S, Klein I: Thyroid hormone and blood pressure regulation. Curr

Hypertension Rep 5: 513-20, 2003.

17.

Fazio S, Palmieri EA, Lombardi G, et al: Effects of thyroid hormone on the

cardiovascular system. Recent Prog Horm Res 59: 31-50, 2004.

18. Almeida JP, Sanabria AH, Lima ENP, Kowalski LP. Late side effects of

radioactive iodine therapy on salivary glands function in patients with thyroid

cancer. Oral Dis 2009, submitted.

5 CONSIDERAÇÕES FINAIS

Em relação a qualidade de vida dos pacientes antes e após a iodoterapia no

estudo II, seguem abaixo detalhados nas tabelas os resultados dos questionários

aplicados. Como não observamos o efeito protetor da amifostina aos efeitos

colaterais da iodoterapia sobre as glândulas salivares os dois grupos passaram a não

apresentar diferenças também nos domínios avaliados pelo questionário UW-QOL.

Tabela 5.1 - “Scores” médios dos 12 domínios e “score” final dos grupos amifostina

e placebo pré-tratamento.

Amifostina Placebo

Média (dp)

p value

Dor

84.1 (20.2) 91.7 (14.8) .28

Aparência

86.4 (17.2) 79.2 (19.6) .33

Atividade

75 (25) 81.9 (18.8) .50

Recreação

81.8 (25.2) 79.2 (24.6) .75

Deglutição

97 (9.9) 94.5 (12.6) .57

Mastigação

95.4 (15.1) 100 (0) .20

Fala

93.9 (20.2) 85.2 (28.5) .27

Ombro

78.7 (30.9) 75.9 (35.8) .88

Paladar

87.8 (27.1) 94.4 (17.2) .55

Saliva

87.9 (22.5) 96.3 (15.8) .12

Humor

81.8 (31.9) 81.9 (31.2) .89

Ansiedade

69.8 (31.5) 76.1 (27.5) .59

“Score” final

84.9 (16.3) 86.4 (10.9) .96

Tabela 5.2 - “Scores” médios dos 12 domínios e “score” final dos grupos amifostina

e placebo pós-tratamento.

Amifostina Placebo

Média (dp)

p value

Dor

88.6 (20.5) 94.4 (13.7) .44

Aparência

90.9 (16.8) 90.3 (19.4) .88

Atividade

81.8 (19.6) 83.3 (17.1) .88

Recreação

93.2 (11.7) 93.1 (16.7) .63

Deglutição

97 (9.9) 96.3 (10.7) .86

Mastigação

100 (0) 97.2 (11.8) .43

Fala

100 (0) 90.8 (25) .16

Ombro

78.7 (30.9) 81.5 (34.7) .70

Paladar

100 (0) 98.2 (7.8) .43

Saliva

90.9 (21.6) 98.2 (7.8) .27

Humor

84.1 (23.1) 93.1 (16.7) .14

Ansiedade

81.9 (22.9) 89 (16) .43

“Score” final

90.6 (9.2) 92.1 (9.8) .73

A diferença em pontos entre os domínios antes e após no Questionário UW-

QOL é considerada clinicamente significativa se for maior ou igual a 7

(VARTANIAN et al. 2004). Como vemos na tabela abaixo, no grupo amifostina em

todos os domínios associados aos efeitos colaterais da iodoterapia houve manutenção

ou melhora no “score” após o tratamento. No grupo placebo observamos melhora em

todos os domínios, com excessão ao domínio mastigação em que o “score” médio foi

negativo indicando piora neste domínio após a iodoterapia. Porém nenhuma destas

diferenças entre os grupos foram significativas.

Tabela 5.3 - Diferença entre os valores pós e pré-tratamento dos domínios que

refletem os efeitos colaterais associados a iodoterapia e “score” final dos grupos

amifostina e placebo.

Amifostina Placebo

Média (dp)

p value

Deglutição

0 (0) 1.8 (7.8) .43

Mastigação

4.5 (15.1) -2.8 (11.8) .15

Paladar

12.2 (27.1) 3.7 (19.4) .39

Saliva

3 (27.8) 1.9 (18) .95

“Score” final

5.6 (11) 5.7 (11.3) .75

Na Tabela 5.4 descrevemos o “status” pós-tratamento em relação aos

domínios associados aos efeitos colaterais da iodoterapia nos pacientes dos grupos

amifostina e placebo comparados ao “status” pré-tratamento.

Tabela 5.4 - Status pós-tratamento em relação aos domínios associados aos efeitos

colaterais da iodoterapia e “score” final nos grupos amifostina e placebo.

Deglutição

Amifostina Placebo

N (%)

Total

N (%)

Manteve

11 (100) 17 (94.4) 28 (96.6)

Melhora

0 (0) 1 (5.6) 1 (3.4)

Piora

- - -

Mastigação

Manteve

10 (90.9) 17 (94.4) 27 (93.1)

Melhora

1 (9.1) 0 (0) 1 (3.4)

Piora

0 (0) 1 (5.6) 1 (3.4)

Paladar

Manteve

9 (81.8) 15 (83.3) 24 (82.8)

Melhora

2 (18.2) 2 (11.1) 4 (13.8)

Piora

0 (0) 1 (5.6) 1 (3.4)

Saliva

Manteve

7 (63.6) 16 (88.9) 23 (79.3)

Melhora

2 (18.2) 1 (5.6) 3 (10.3)

Piora

2 (18.2) 1 (5.6) 3 (10.3)

“Score” final

Manteve

2 (18.2) 1 (5.6) 3 (10.3)

Melhora

6 (54.5) 13 (72.2) 19 (65.5)

Piora

3 (27.3) 4 (22.2) 7 (24.1)

Com estes resultados podemos afirmar que os efeitos colaterais da

iodoterapia sobre as glândulas salivares não apresentam impacto na qualidade de

vida destes pacientes no período de 3 meses. Como vimos no estudo I, o impacto na

qualidade de vida dos efeitos colaterais da iodoterapia são tardios, geralmente 2 anos

após o término do tratamento, afetando principalmente o domínio de deglutição. Para

verificar se a amifostina apresenta algum efeito protetor sobre as glândulas salivares

em pacientes submetidos a iodoterapia a médio e longo prazo será necessário

acompanhar estes pacientes, e com isto poder-se-á avaliar também se a amifostina

diminui o impacto destes efeitos colaterais sobre a qualidade de vida destes

pacientes.

6 CONCLUSÕES

Com os resultados apresentados acima, podemos concluir que:

Os efeitos do

131

I sobre as glândulas salivares possivelmente ocorrem sobre os

ductos salivares resultando em constrição ductal, devido à fibrose periductal

induzida pela radiação, dificultando assim a eliminação da saliva produzida e

resultando em quadros de xerostomia e sialodenite.

Esta constrição ductal com resultante retenção salivar é um dos mecanismos

responsáveis pela ocorrência de sialodenite crônica tardia em alguns

pacientes.

O uso de pilocarpina para o tratamento de xerostomia em pacientes

submetidos a iodoterapia não se mostrou viável, devido aos efeitos colaterais

associados ao medicamento.

Alterações nas funções de mastigação, deglutição e fala verificadas pelo

questionário de qualidade de vida aplicado, em pacientes que receberam doses

acima de 150 mCi

131

I, impactam na qualidade de vida dos pacientes

submetidos a iodoterapia pode ser verificado normalmente dois anos após o

tratamento, sugerindo que a falta de saliva pode impactar na fase oral da

deglutição.

A incidência de efeitos colaterais agudos do

131

I sobre as glândulas salivares

na nossa população é muito semelhante à descrita na literatura.

6. Nas condições e população estudadas, em relação a dose e via de

administração, a amifostina não se mostrou eficaz na prevenção de efeitos

colaterais do

131

I sobre as glândulas salivares a curto prazo.

Este estudo ressalta as particularidades e alto risco da adimistração

endovenosa da amifostina em paciente hipotireoideanos.

A iodoterapia não apresenta impacto a curto prazo sobre a qualidade de vida

dos pacientes incluídos no protocolo do estudo II/amifostina.

7 REFERÊNCIAS BIBLIOGRÁFICAS

Aframian DJ, Helcer M, Livni D, Markitziu A. Pilocarpine for the treatment of

salivary glands’ impairment caused by radioiodine therapy for thyroid cancer.

Oral

Dis 2006; 12:297-300.

Alexander C, Bader JB, Schaefer A, Finke C, Kirsch CM. Intermediate and long-

term side effects of high-dose radioiodine therapy for thyroid carcinoma.

J Nucl

Med 1998; 39: 1551-54.

Allweiss P, Braunstein GD, Katz A, Waxman A. Sialadenitis following I-131 therapy

for thyroid carcinoma: concise communication.

J Nucl Med 1984; 25:755-58.

Anné PR, Machtay M, Rosenthal DI, et al. A phase II trial of subcutaneous

amifostine and radiation therapy in patients with head and neck cancer.

Int Radiat

Oncol Biol Phys 2007; 67:445-52.

Antonadou D, Pepelassi M, Synodinou M, Puglisi M, Throuvalas N. Prophylatic use

of amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in

head and neck cancer.

Int Radiat Oncol Biol Phys 2002; 52:739-47.

Bardet E, Martin L, Calais G, et al. Preliminary data of the GORTEC 2000-02 phase

III trial comparing intravenous and subcutaneous administration of amifostine for

head and neck tumors treated by external radiotherapy.

Semin Oncol 2002; 29:57-

60.

Blumberg AL, Nelson DF, Gramkowski M, et al. Clinical trials of WR-2721 with

radiation therapy.

Int J Radiat Oncol Biol Phys 1982; 8:561-3.

Bohuslavizki KH, Brenner W, KlutmannS, et al. Radioprotection of salivary glands

by amifostine in high-dose radioiodine therapy.

J Nucl Med 1998a; 39:1237-42.

Bohuslavizki KH, Klutmann S, Brenner W, Mester J, Henze E, Clausen M. Salivary

gland protection by amifostine in high-dose radioiodine treatment: results of a

double-blind placebo-controlled study.

J Clin Oncol 1998b; 16:3542-49.

Bohuslavizki KH, Klutmann S, Jenicke L, et al. Radioprotection of salivary glands

by S-2-(3-aminopropylamino)-ethylphosphorothioic (amifostine) obtained in a rabbit

animal model.

Int J Radiat Oncol Biol Phys 1999; 45:181-86.

Bonner HS, Shaw LM. New dosing regimens for amifostine: a pilotstudy to compare

the relative bioavailability of oral and subcutaneous administration with intravenous

infusion.

J Clin Pharmacol 2002; 42:166-74.

Brizel DM, Wasserman TH, Henke M, et al. Phase III randomized trial of amifostine

as a radioprotector in head and neck cancer.

J Clin Oncol 2000; 18:3339-45.

Bushnell DL, Boles MA, Kaufman GE, Wadas MA, Barnes E. Complications,

sequela and dosimetry of iofine-131 therapy for thyroid carcinoma.

J Nucl Med

1992; 33:2214-21.

Caglar M, Tuncel M, Alpar R. Scintigraphic evaluation of salivary gland dysfunction

in patients with thyroid cancer after radioiodine treatment.

Clin Nucl Med 2002;

27:767-71.

Crevenna R, Zettinig G, Keilani M, et al. Quality of life in patients with non-

metastatic differentiated thyroid carcinoma under thyroxine supplementation therapy.

Supp Care Cancer 2003; 11: 597-603.

Dagan T, Bedrin L, Horowitz Z, et al. Quality of life of well-differentiated thyroid

carcinoma patients.

J Laryngol Otol 2004; 118:537-42.

Glick JH, Glover D, Weiler C, et al. Phase I clinical trials of WR-2721 with

alkylanting agent chemotherapy.

Int J Radiat Oncol Biol Phys 1982; 8:575-80.

Goolden AWG, Mallard JR, Farran HEA. Radiation sialitis following radioiodine

therapy.

Br J Radiol 1957; 30: 210-12.

Gosrky M, Epstein JB, Parry J, Epstein MS, Le ND, Silverman SJr. The efficacy of

pilocarpine in cancer patients with hyposalivation following radiation therapy.

Oral

Surg Oral Med Oral Pathol 2004; 97:190-5.

Haddad P, Karimi M. A randomized, double-blind, placebo-controlled trial of

concomitant pilocarpine with head and neck irradiation for prevention of radiation-

induced xerostomia.

Radiat Oncol 2002; 64:29-32.

Hamlar DD, Schuller DE, Gahbauer RA, et al. Determination of the efficacy of

topical oral pilocarpine for postradiation xerostomia in patients with head and neck

carcinoma.

Laryngoscope 1996; 106:972-76.

Helman J, Turner RJ, Fox PC, Baum BJ.

99m

Tc-pertechnetate uptake in parotid acinar

cells by the Na

/Cl

co-transport system. J Clin Invest 1987; 79:1310-13.

Horiot JC, Lipinski F, Schraub S, et al. Post-radiation sever xerostomia relieved by

pilocarpine: a prospective French cooperative study.

Radiat Oncol 2000; 55: 233-

39.

Huang SM, Lee CH, Chien LY, Liu HE, Tai CJ. Postoperative quality of life among

patients with thyroid cancer.

J Advanced Nursing 2004; 47:492-99.

Jemal A, Siegel R, Ward E, et al. Cancer Statistics.

CA Cancer J Clin 2008; 58:71-

96.

Jensen SB, Pedersen AM, Reibel J, Nauntofte B. Xerostomia and hypofunction of

the salivary glands in cancer therapy.

Support Care Cancer 2003; 11:207-25.

Jhiang SM, Cho JY, Ryu KY, et al. An immunohistochemical study of Na

symporter in human thyroid tissues and salivary gland tissues.

Endocrinol 1998;

139: 4416-9.

Kim SJ, Choi HY, Kim IJ, et al. Limited cytoprotective effects of amifostine in high-

dose radioactive iodine 131-treated well-differentiated thyroid cancer patients:

analysis of quantitative salivary scan.

Thyroid 2008; 18:325-31.

Koseki M, Maki Y, Matsukubo T, Ohashi Y, Tsubota K. Salivary flow and its

relationship to oral signs and symptoms in patients with dry eyes.

Oral Dis 2004;

10:75-80.

Koukourakis MI, Kyrias G, Kakolyris S, et al. Subcutaneous administrations of

amifostine during fractionated radiotherapy: a randomized phase II study.

J Clin

Oncol 2000; 18:2226-33.

Law A, Kennedy T, Pellitteri P, Wood C, Christie D, Yumen O. Efficacy and safety

of subcutaneous amifostine in minimizing radiation-induced toxicities in patients

receiving combined-modality treatment for squamous cell carcinoma of the head and

neck.

Int J Radiat Oncol Biol Phys 2007; 69:1361-8.

Leek H, Albertsson M. Pilocarpine treatment of xerostomia in head and neck

patients.

Micron 2002; 33:153-5.

LeVeque FG, Montgomery M, Potter D, et al. A multicenter, randomized, double-

blind, placebo-controlled, dose-titration study of oral pilocarpine for treatment of

radiation-induced xerostomia in head and neck cancer patients.

J Clin Oncol 1993;

11:1124-31.

Maier H, Bihl H. Effect of radioactive iodine therapy on parotid gland function.

Acta

Otolaryngol (Stockh) 1987; 103:318-24.

100

Malpani BL, Samuel AM, Ray S. Quantification of salivary gland function in thyroid

cancer patients treated with radioiodine.

Int J Radiat Oncol Biol Phys 1996;

35:535-40.

Mandel SJ, Mandel L. Radioactive iodine and the salivary glands.

Thyroid 2003;

13:265-71.

Martinez JR, Cassity N. Cl

requirement for saliva secretion in isolated, perfused rat

submandibular gland.

Am J Physiol 1985; 249: G464-G469.

Mason DK, Harden RMcG, Alexander WD. The salivary and thyroid glands: a

comparative study in man.

Br Dent J 1967; 122:485-89.

Mazzaferri EL. An overview of the management of papillary and follicular thyroid

carcinoma.

Thyroid 1999; 9:421-27.

Menard TW, Izuisu KT, Ensign WY, Keller PJ, Morton TH, Truelove EL.

Radioprotection by WR-2721 of gamma-irradiated rat parotid gland: effect on gland

weight and secretion at 8-10 days post irradiation.

Int J Radiat Oncol Biol Phys

1984; 10:1555-9.

Mendoza A, Shaffer R, Karakla D, Mason ME, Elkins D, Goffman TE. Quality of

life with well-differentiated thyroid cancer: treatment toxicities and their reduction.

Thyroid 2004; 14:133-40.

Mosqueda-Taylor A, Ortiz KL, Camacho MEI, Franco MAD, Muñoz AMC. Efecto

del clorhidrato de pilocarpina como estimulante de la producción salival en pacientes

sometidos a radioterapia de cabeza y cuello.

Med Oral 2004; 9:204-11.

Nakada K, Ishibashi T, Takei T, et al. Does lemon candy decrease salivary gland

damage after radioiodine therapy for thyroid cancer?

J Nucl Med 2005; 46:261-6.

101

Newkirk KA, Ringel MD, Wartofsky L, Burman KD. The role of radioactive iodine

in salivary gland dysfunction.

ENT J 2000; 79:460-68.

Olmos RAV, Keus RB, Takes RP, van Tinteren H, Baris G, Hilgers FJM, et al.

Scintigraphic assessment of salivary function and excretion response in radiation-

induced injury of the major salivary glands.

Cancer 1994; 73:2886-93.

Ozsahin M, Betz M, Matzinger O, et al. Feasibility and efficacy of subcutaneous

amifostine therapy in patients with head and neck cancer treated with curative

accelerated concomitant-boost radiation therapy.

Arch Otolaryngol Head Neck

Surg 2006; 132:141-5.

Pratt NE, Sodicoff M, Liss J, David M, Sinesi M. Radioprotection of the rat parotid

gland by WR-2721: morphology at 60 days post-irradiation.

Int J Radiat Oncol Biol

Phys 1980; 6:431-5.

Rades D, Fehlauer F, Bajrovic A, Mahlmann B, Richter E, Alberti W. Serious

adverse effects of amifostine during radiotherapy in head and neck cancer patients.

Radiat Oncol 2004; 70:261-4.

Rigler RG, Scanlon PW. Radiation parotitis from radioactive iodine therapy.

Staff

Meet Mayo Clin 1955; 30:149-53.

Shaw LM, Bonner Hs, Schuchter L, Schiller J, Lieberman R. Pharmacokinectis of

amifostine: effects of dose and method of administration.

Semin Oncol 1999; 26:34-

Silberstein EB. Reducing the incidence of

131

I-induced sialadenitis: the role of

pilocarpine.

J Nucl Med 2008; 49:546-9.

Tan LGL, Nan L, Thumboo J, Sundram F, Tan LKS. Health-related quality of life in

thyroid cancer survivors.

Laryngoscope 2007; 117:507-10.

102

Utley JF, Phillips TL, Kane LJ. Protection of normal tissues by WR-2721 during

fractionated irradiation.

Int J Radiat Oncol Biol Phys 1976; 1:699-703.

Utley JF, Quinn CA, White FC, Seaver NA, Bloor CM. Protection of normal tissue

against late radiation injury by WR-2721.

Radiat Res 1981; 85:408-15.

Vartanian JG, Carvalho AL, Yueh B, et al. Long-term quality-of-life evaluation after

head and neck cancer treatment in a developing country.

Arch Otolaryngol Head

Neck Surg 2004; 130:1209-13.

Vartanian JG, Carvalho AL, Yueh B, et al. Brazilian-Portuguese validation of the

University of Washington quality of life questionnaire for head and neck cancer

patients.

Head Neck 2006; 28:1115-21.

Vayre L, Sabourin JC, Caillou B, et al. Immunohistochemical analysis of Na

symporter distribution in human extra-thyroidal tissues.

Eur J Endocrinol 1999;

141: 382-6.

WHOQOL Group. Study protocol for the World Health Organisation project to

develop a quality of life assessment instrument (the WHOQOL).

Qual Life Res

1993; 2:153-9.

Wiesenfeld D, Webster G, Ferguson MM, MacFadyen EE, MacFarlane TW. Salivary

gland dysfunction following radioactive iodine therapy.

Oral Surg Oral Med Oral

Pathol 1983; 55:138-41.

Woolley PV, Ayood MJ, Smith FP, Dritschilo A. Clinical trial of the effect of S-2-

(3-aminopropylamino)-ehtylphosphorothioic acid (WR-2721)(NSC 296961) on the

toxicity of cyclophosphamide.

J Clin Oncol 1983; 1:198-203.

103

Zimmerman RP, Mark RJ, Tran LM, Juillard GF. Concomitant pilocarpine during

head and neck irradiation is associated with decreased posttreatment xerostomia.

Int

J Radiat Oncol Biol Phys 1997; 37:571-5.

Anexo 1 – TCLE estudo I

Anexo 2 – Aprovação CEP Fundação Antônio Prudente

Anexo 3 – Questionário

Anexo 4 – Ficha avaliação do tratamento com pilocarpina

AVALIAÇÃO DO TRATAMENTO COM PILOCARPINA

NOME:__________________________________________________________________

RGH:____________________________________________________________________

DATA INÍCIO TTO:_______________________________________________________

DOSE 5mg 3X AO DIA

Marque com um X o sintoma no dia respectivo:

Sintomas apresentados D1 D2 D3 D4 D5 D6 D7

Suor excessivo

Aumento da freqüência urinária

Lacrimejamento

Calafrios

Fraqueza

Tontura

Náusea

Dor de cabeça

Hipertensão arterial

Taquicardia

Descreva aqui qualquer outro sintoma apresentado não relacionado na

tabela acima:

Anexo 5 – TCLE estudo II

Anexo 6 – Aprovação CEP Fundação Pio XII

Anexo 7 – Tabela de randomização

Tabela para 60 pacientes

NÚMEROS PARES – grupo amifostina

NÚMEROS ÍMPARES – grupo placebo

SEQUÊNCIA DE LEITURA – linhas

Tabela gerada pelo programa Epi Info versão 6.04 Janeiro 2001 Center of Disease

Control and Prevention (CDC) - USA

ORIGINAL ARTICLE

Clinical Predictors of Quality of Life in Patients

With Initial Differentiated Thyroid Cancers

Juliana Almeida, DDS, MSc; Jose´ Guilherme Vartanian, MD, PhD; Luiz Paulo Kowalski, MD, PhD

Background: Patients with differentiated thyroid

cancer (DTC) usually have a good prognosis. Tradi-

tionally, treatment success in patients with cancer has

been evaluated by survival time. Recently, it has been

observed that the diagnosis and treatment of cancer

also have a strong effect on the quality of life (QOL) of

these patients.

Objective: To assess the QOL of patients with DTC and

its potential clinical predictors.

Design: Cross-sectional analysis.

Setting: A tertiary cancer institution.

Patients: One hundred fifty-four patients submitted to

thyroidectomy (1997-2006) were evaluated using the Uni-

versity of Washington Quality of Life questionnaire.

Main Outcome Measures: Descriptive analysis of the

results was done, as bivariate and multivariate analyses

to compare each independent variable with each of 13

QOL domains.

Results: Patients 45 years or younger had better recre-

ation scores than did patients older than 45 years (P=.04).

Thirty-eight patients were submitted to neck dissec-

tion. Patients submitted to modified radical neck dissec-

tion reported worse chewing and shoulder scores than

did patients submitted to selective paratracheal lymph

node dissection only and those without neck dissection

(P = .003 and P =.004, respectively). Patients who re-

ceived more than 150 mCi of radioactive iodine therapy

(RIT) reported significantly worse pain, swallowing, chew-

ing, speech, taste, anxiety, and composite scores. Co-

morbidities showed significant effect on recreation, ac-

tivity, speech, saliva, and composite scores (P =.02,

P=.046, P=.02, P= .01, and P=.008, respectively). In mul-

tivariate analysis, RIT is the only variable associated with

a worse composite score (P=.003).

Conclusion: Although QOL after treatment of thyroid

cancer can be considered good for most patients, those

submitted to RIT at doses higher than 150 mCi are at risk

for poor QOL and, therefore, may need more intensive

follow-up and treatment.

Arch Otolaryngol Head Neck Surg. 2009;135(4):342-346

ATIENTS WITH DIFFERENTI-

ated thyroid cancer (DTC),

in general, have a very good

prognosis, and overall long-

term survival is higher than

90%, with variations in subsets of pa-

tients.

1,2

In DTC, surgery is the therapy of

choice. Surgical options include lobec-

tomy with isthimectomy or total thyroid-

ectomy with or without neck lymph node

dissection. The choice of procedure is af-

fected by well-defined prognostic fac-

tors.

3,4

Ablative surgery of the thyroid and

possible neck disease and postoperative ra-

dioactive iodine therapy (RIT) result in

prolonged survival but may lead to voice

alterations, dysphagia, sialadenitis, taste

disturbance, and xerostomia.

5-7

Traditionally, the main outcome mea-

sure in oncology patients has been sur-

vival, based on tumor control, but re-

cently it has been increasingly recognized

that the diagnosis and management of can-

cer can have a major effect on every as-

pect of the quality of life (QOL) of a pa-

tient.

The aims of cancer treatment

became not only to increase survival but

also to preserve QOL,

and measuring these

changes has been considered to be of para-

mount importance.

1,8

The QOL is defined as the perceptions

of an individual regarding his or her po-

sition in life in the context of the culture

and value systems in which he or she lives

and in relation to his or her goals, expec-

tations, standards, and concerns (WHO-

QOL, 1993).

Health-related QOL (HR-

QOL) refers to a multidimensional concept

that encompasses perception of negative

and positive aspects of physical, emo-

tional, social, and cognitive functions,

which could be affected by the disease or

its treatment.

Several instruments have

been developed to assess QOL in patients

Author Affiliations:

Department of Head and Neck

Surgery and Otorhinolaryngol-

ogy, Hospital A. C. Camargo,

Sa˜o Paulo, Brazil.

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 135 (NO. 4), APR 2009 WWW.ARCHOTO.COM

342

at Capes Consortia, on May 18, 2009 www.archoto.comDownloaded from

Anexo 8 - Artigo publicado

with head and neck cancer. Among them, the Univer-

sity of Washington Quality of Life (UW-QOL) question-

naire is a validated, accurate, and internationally ac-

cepted survey instrument. The use of such a questionnaire

allows the evaluation of HR-QOL and leads to a better

understanding of the patient’s expectations.

8,11

In the past 20 years, an increasing number of studies

have measured QOL as an end point in the evaluation of

the effect of the disease and its treatment on the daily life

of the patient.

6,8

However, there have been relatively few

HR-QOL studies looking specifically at patients with thy-

roid cancer.

1,10,11

The aims of this study are to assess QOL

in patients with DTC and to evaluate whether different

modalities of treatment can interfere in the QOL of these

patients.

METHODS

DESIGN

A cross-sectional analysis was performed of adults with initial

DTC treated with total thyroidectomy, some of whom had un-

dergone adjuvant RIT, between January 1, 1997, and Decem-

ber 31, 2006, at a single tertiary cancer institution. Patients who

had received previous head and neck radiation therapy or had

sicca syndrome symptoms were excluded. The study was ap-

proved by the ethics committee of Hospital A. C. Camargo, and

all participants signed an informed consent form.

The patients were invited to participate in this study at their

follow-up medical consultation. All of them had normal thyroid

hormone levels, and patients who had ended treatment 4 months

to 10 years before (median, 2 years) were included. The inde-

pendent variables were age, sex, time since treatment, RIT dose,

neck dissection, and comorbidities. The dependent variables were

the 13 QOL scales from the UW-QOL questionnaire.

SAMPLE

Four hundred patients who met the inclusion criteria were in-

vited to participate in this study. Of those, 184 patients agreed

to participate and 154 completed the questionnaire and had clini-

cal stage I or II tumors. A total of 137 patients (89.0%) were

women, and 17 (11.0%) were men; the mean patient age was

46.9 years (median age, 46 years; age range, 21-87 years). All

the patients underwent a total thyroidectomy, and 38 patients

were also submitted to a neck dissection of levels II through

IV (2 patients), II through VI (9 patients), and VI (27 pa-

tients). One hundred fifty-one patients had papillary carci-

noma and 3 had follicular carcinoma. Regarding clinical stage,

85.1% of tumors were in stage I and 14.9% were in stage II.

Ninety-three patients (60.4%) underwent RIT, and the me-

dian dose was 130 mCi (range, 30-700 mCi). Seventy-three pa-

tients received doses up to 150 mCi, and 20 patients received

doses higher than 150 mCi. Comorbidities were evaluated using

the American Society of Anesthesiologists (ASA) classifica-

tion in 137 patients. Thirty-eight patients were classified as ASA

I, 97 as ASA II, and 2 as ASA III. These data are summarized in

Table 1.

MEASURES

Demographic measures included age (Յ45 or Ͼ45 years) and

sex. Age 45 years was used as a reference owing to its impor-

tant prognostic value in patients with DTC. The classification

of neck dissection was paratracheal (level VI), radical (levels

II-IV), and extended radical (levels II-VI). At the analysis, these

patients were grouped as none (no neck dissection), paratra-

cheal (neck dissection of level VI), and radical (neck dissec-

tion of levels II-IV and II-VI).

Many studies

5,12-14

have discussed that radioactive iodine ef-

fects are dose dependent, and a recent study by us showed that

doses higher than 150 mCi are associated with more adverse ef-

fects on the salivary glands. In this way, we categorized the vari-

able RIT as patients who were not submitted to RIT, patients who

received up to 150 mCi, and those who received more than 150

mCi. Time since treatment was measured in months and was cat-

egorized into 12 months or less and more than 12 months.

The physical status classification of the ASA

(I, healthy pa-

tients, no medical problems; II, mild systemic disease; III, se-

vere systemic disease but not incapacitating; IV, severe sys-

temic disease that is a constant threat to life; and V, moribund,

not expected to survive without the operation) was used to grade

the comorbidities of the patients and to associate them with

the QOL of these patients. See Table 1 for details.

QOL ASSESSMENT

A Brazilian-Portuguese version of the UW-QOL questionnaire vali-

dated by Vartanian et al

was used. The UW-QOL question-

naire was designed as a self-reported scale and, for this reason,

the patients completed it by themselves. Patients who did not feel

able to complete the UW-QOL questionnaire independently were

helped by their companion. The UW-QOL questionnaire was ap-

plied during 2006 in days reserved for only this study.

The questionnaire consists of 12 questions that evaluate the

following domains: pain, appearance, activity, recreation, chew-

ing, swallowing, speech, shoulder, taste, saliva, humor, and anxi-

ety. Scores can range from 0 to 100, with 100 indicating the

best level of overall function. The composite score is the mean

of the scores of all 12 domains. There is general agreement that

a composite score of 75 to 100 has little effect on QOL, a score

of 50 to 74 has a relative effect on QOL, and a score less than

50 has an important effect on QOL. Three general questions

Table 1. Demographic and Treatment Variables

Variable Patients, No. (%) (N=154)

Age, y

Յ45 73 (47.4)

Ͼ45 81 (52.6)

Sex

Male 17 (11.0)

Female 137 (89.0)

RIT

None 61 (39.6)

Յ150 mCi 73 (47.4)

Ͼ150 mCi 20 (13.0)

Neck dissection

None 116 (75.3)

Paratracheal 27 (17.5)

Radical 11 (7.1)

Clinical stage

I 131 (85.1)

II 23 (14.9)

ASA classification

I 38 (27.7)

II 97 (70.8)

III 2 (1.5)

Abbreviations: ASA, American Society of Anesthesiologists;

RIT, radioactive iodine therapy.

Only 137 patients provided this information.

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 135 (NO. 4), APR 2009 WWW.ARCHOTO.COM

343

at Capes Consortia, on May 18, 2009 www.archoto.comDownloaded from

evaluate overall QOL and HR-QOL. We scored the individual

domains according to the UW-QOL questionnaire guidelines.

STATISTICAL ANALYSES

Statistical analysis was performed using a software program (SPSS

for Windows version 15.0; SPSS Inc, Chicago, Illinois). A de-

scriptive analysis of the results was performed. Bivariate analy-

ses were conducted by comparing each of the independent vari-

ables of age, sex, neck dissection, RIT, time since treatment,

and comorbidities with each of the 13 QOL scales on the UW-

QOL questionnaire using nonparametric Mann-Whitney or

Kruskal-Wallis tests. To determine significant predictors of QOL

controlling for one another, multivariate analysis was con-

ducted using multiple linear regression.

RESULTS

In answering the UW-QOL questionnaire on overall

health, 94.4% of patients reported that their health was

the same or better than it was before treatment, 83.9%

of patients reported good HR-QOL, and 83.3% of pa-

tients reported good general QOL. There were no sig-

nificant differences in these questions regarding age, sex,

RIT, neck dissection, or comorbidities. The median com-

posite score was 93.05 (range, 53.5-100), which is asso-

ciated with good QOL.

BIVARIATE ANALYSES

In the evaluation of demographic variables, age had an

effect on the recreation domain, with patients older than

45 years showing worse scores than younger patients

(P=.04). In regard to the other domains, age did not have

a significant association. In the same way, sex did not have

an effect on any domain (

Table 2).

The RIT had an effect on many domains, and doses

higher than 150 mCi had a strong association with worse

scores in several domains, such as pain (P=.045), swal-

lowing (P=.03), chewing (PϽ .001), speech (P=.004),

shoulder (P=.04), taste (P=.006), anxiety (P= .004), and

composite score (P=.01). Patients submitted to neck dis-

section from level II through VI had significantly worse

chewing scores (P=.003) and shoulder scores (P=.004).

Time since treatment was not associated with worse scores

in any domain. Patients classified as ASA II and III had

worse scores in the activity (P=.05), recreation (P=.02),

speech (P=.02), and saliva (P=.01) domains and in the

composite score (P=.008). All these data are summa-

rized in Table 2.

MULTIVARIATE ANALYSES

To conserve power and because sex and time since treat-

ment were not significant in the bivariate analyses, these

variables were omitted from the multivariate analyses. Vari-

ables with PՅ .25 were considered in multiple linear re-

gression to determine the greatest predictor of QOL in pa-

tients with thyroid cancer controlling for one another.

The RIT was the strongest predictor factor, affecting

domains such as chewing, speech, taste, saliva, and anxi-

ety. It was the only variable that affected the composite

Table 2. Bivariate Associations Between Demographic and Treatment Variables and Each Function Domain and the Composite Score

of the UW-QOL Questionnaire

Variable

Domain Score, Mean

Pain Appearance Activity Recreation Swallowing Chewing Speech Shoulder Taste Saliva Humor Anxiety

Composite

Score

Age, y

Յ45 94.5

Ͼ45 90.1

P value .74 .26 .29 .04 .19 .57 .89 .90 .15 .23 .33 .26 .06

Sex

Male

Female

P value .06 .09 .45 .83 .11 .89 .83 .11 .31 .42 .55 .77 .05

RIT

None 86.5 95.9 98.4 98.4 89.6 96.7 88.0 91.6

Յ150 mCi 88.0 96.8 99.3 98.6 85.9 94.6 89.6 91.8

Ͼ150 mCi 76.3 90.1 87.5 91.8 71.7 85.1 76.9 84.0

P value .05 .56 .12 .52 .03 Ͻ.001 .004 .04 .006 .20 .65 .004 .01

Neck dissection

None 98.3 86.8

Paratracheal 98.2 90.2

Radical 94.0 60.7

P value .86 .15 .77 .55 .32 .003 .33 .004 .83 .94 .19 .09 .56

Time since treatment, mo

Յ12

Ͼ12

P value .88 .61 .74 .20 .72 .64 .50 .57 .58 .20 .14 .71 .56

ASA classification

I 91.5 94.1 97.4 95.7 93.2

II 85.6 92.3 98.6 90.1 90.0

III 75.0 62.5 83.5 67.0 83.4

P value .24 .15 .05 .02 .13 .78 .02 .34 .35 .01 .47 .33 .008

Abbreviations: ASA, American Society of Anesthesiologists; RIT, radioactive iodine therapy; UW-QOL, University of Washington Quality of Life.

Mean values are shown for statistically significant variables only.

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 135 (NO. 4), APR 2009 WWW.ARCHOTO.COM

344

at Capes Consortia, on May 18, 2009 www.archoto.comDownloaded from

score. The presense of comorbidities, as measured by ASA

classification, was the second predictor of worse QOL;

it affected domains such as recreation, speech, and sa-

liva. Neck dissection affected chewing and shoulder scores,

and age affected recreation scores. The data are summa-

rized in

Table 3 with the value of unstandardized co-

efficient B and each P value.

COMMENT

In this study, in univariate and multivariate analyses, the

greatest predictor of QOL in patients with thyroid can-

cer was RIT dose, with higher doses showing decreased

QOL through the composite score. The composite score

shows the effect of all the domains evaluated, and worse

scores in specific domains will reflect on the final score.

Functions such as taste, speech, chewing, and swallow-

ing are strongly associated with RIT salivary gland ef-

fects, as is seen through the association between RIT and

these domains in the UW-QOL questionnaire. Until now,

in the literature review, none of the published studies

showed the effect of RIT or doses of radioactive iodine

on QOL in the patient with thyroid cancer. This is an im-

portant finding because the indication of RIT should also

consider the late effects of the treatment.

The adverse effects of RIT are well recognized and, in

general, are mild and self-limiting; severe complications are

rare enough that the benefit of therapy typically out-

weighs its risk.

17,18

The common acute adverse effects re-

ported are nausea, vomiting, epigastralgia, taste distur-

bance, and sialadenitis,

and the late adverse effects

normally restrict themselves to the salivary glands as si-

aladenitis and xerostomia.

Recent findings from our group

reinforce the hypothesis of Maier and Bihl

that patients

submitted to RIT have an impairment in the ability to drain

the saliva, and it reflects as clinical dysphagia.

Considering that many patients with DTC are sub-

mitted to RIT, the effect of those specific adverse effects

and those resulting from the surgical procedure on the

QOL of such patients were not previously extensively de-

scribed. There have been relatively few and recent HR-

QOL studies looking specifically into patients with thy-

roid cancer.

1,2,10,11,20-23

The paucity of specific instruments

to assess the QOL of patients with thyroid cancer asso-

ciated with low mortality and morbidity rates of the treat-

ment can explain why there are so few studies in this field.

Most published studies use the 36-Item Short Form

Health Survey, that is, a generic QOL instrument, and

do not have specific domains to evaluate the effect of pos-

sible adverse effects of treatment. The UW-QOL ques-

tionnaire, although not commonly used in patients with

thyroid cancer, has value in predicting QOL in these pa-

tients because it makes it possible to evaluate points that

can be related to adverse effects of surgery and RIT.

The main postoperative complications of thyroidec-

tomy are vocal cord palsy owing to dysfunction of the

recurrent laryngeal nerve and hypocalcemia. Neck dis-

section and paratracheal lymph node dissection, when

associated with total thyroidectomy, were significantly

associated with transitory and permanent hypocalce-

mia.

Besides those results, swallowing changes and oc-

casional dysphagia are sequelae reported after thyroid re-

section, even long after the surgical procedure.

Neck dissection was associated with chewing function

instead of swallowing function, as is commonly reported

in the literature, owing to injury of the recurrent nerve. As

expected, neck dissection affected the shoulder domain of

the QOL instrument. Preexistent comorbidities are asso-

ciated with a decreased recreation score, as was expected,

and with the domains of speech and saliva. Worse scores

on these last domains associated with the presence of co-

morbidities probably can be explained by the intake of medi-

cations that can interfere with salivary flow.

To our knowledge, only 1 study

has evaluated the

results of the adverse effects of surgery and RIT on such

patients. This study

used a UW-QOL questionnaire that

was adapted but not validated. The authors evaluated 20

patients with thyroid cancer and reported that those older

than 45 years had worse general health, appearance, and

chewing scores but did not show an association of RIT

or neck dissection with any domain.

Different from the data of Dagan et al,

the present

patients reported a good general QOL, with a slight effect

of treatment on their HR-QOL. However, our patients who

were older than 45 years had worse recreation scores, and

preexistent comorbidities had an effect on the activity,

Table 3. Multiple Linear Regression With the Significant Variables From the Bivariate Analyses

Variable Pain Appearance Activity Recreation Swallowing Chewing Speech Shoulder Taste Saliva Humor Anxiety

Composite

Score

Age, y

Յ4.03

(−5.899)Ͼ4

RIT

None/Յ150 mCi .001

(−9.358)

.02

(−4.705)

.004

(−10.889)

.01

(−10.925)

.05

(−10.960)

.003

(−7.182)Ͼ150 mCi

Neck dissection

None/paratracheal .03

(−7.700)

.006

(−22.205)Radical

ASA classification

I/II .01

(−27.560)

.004

(−15.384)

.04

(−23.786)III

Abbreviations: ASA, American Society of Anesthesiologists; RIT, radioactive iodine therapy.

The values are the P value (B value) to the 95% confidence interval.

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 135 (NO. 4), APR 2009 WWW.ARCHOTO.COM

345

at Capes Consortia, on May 18, 2009 www.archoto.comDownloaded from

recreation, speech, and saliva domains. The greatest effect

on QOL with specific domains was the dose of RIT. Pa-

tients submitted to doses higher than 150 mCi had many

domains affected, such as pain, swallowing, chewing,

speech, taste, anxiety, and composite score. Morbidities

of the surgery are detected in chewing and shoulder func-

tions. Time since treatment and sex were not associated

with alterations in QOL.

These results reveal that despite patients with thy-

roid cancer having a good general QOL, there is a sub-

set of patients who live with some comorbidities of the

cancer treatment. The dose of RIT can affect specific ac-

tivities in the daily lives of these patients. The effects of

RIT on specific functions had not been assessed and re-

ported in the literature until now, and more studies are

needed to confirm these findings. Certainly, this study

has some limitations because it is a cross-sectional study,

and there is neither a baseline QOL score before treat-

ment nor follow-up across time. Evaluation of QOL at

different points in time after treatment could be another

limitation, but at the time of the analysis it seems not to

have affected the results. Prospective studies using vid-

eofluoroscopy to evaluate the different phases of swal-

lowing and salivary gland function in patients receiving

more than 150 mCi of RIT can contribute to the clarifi-

cation of these findings.

Submitted for Publication: April 15, 2008; final revi-

sion received December 5, 2008; accepted December 8,

2008.

Correspondence: Luiz Paulo Kowalski, MD, PhD, De-

partment of Head and Neck Surgery and Otorhinolaryn-

gology, Hospital A. C. Camargo, Rua Professor Antoˆnio

Prudente, 211, 01509-900 Sa˜o Paulo, Brazil (lp_kowalski

@uol.com.br).

Author Contributions: All authors had full access to all

the data in the study and take responsibility for the in-

tegrity of the data and the accuracy of the data analysis.

Study concept and design: Almeida, Vartanian, and

Kowalski. Acquisition of data: Almeida. Analysis and in-

terpretation of data: Almeida and Vartanian. Drafting of

the manuscript: Almeida. Critical revision of the manu-

script for important intellectual content: Vartanian and

Kowalski. Statistical analysis: Vartanian. Obtained fund-

ing: Almeida and Kowalski. Administrative, technical, and

material support: Kowalski. Study supervision: Vartanian

and Kowalski.

Financial Disclosure: None reported.

Funding/Support: This study was funded by grants

05/60474-0 and 06/50061-2 from the Fundac¸a˜o de Am-

paro à Pesquisa do Estado de Sa˜o Paulo.

Previous Presentation: This study was presented at the

Seventh International Conference on Head and Neck Can-

cer of the American Head and Neck Society; July 21-23,

2008; San Francisco, California.

REFERENCES

1. Tan LGL, Nan L, Thumboo J, Sundram F, Tan LKS. Health-related quality of life

in thyroid cancer survivors. Laryngoscope. 2007;117(3):507-510.

2. Huang SM, Lee CH, Chien LY, Liu HE, Tai CJ. Postoperative quality of life among

patients with thyroid cancer. J Adv Nurs. 2004;47(5):492-499.

3. Mazzaferri EL. An overview of the management of papillary and follicular thyroid

carcinoma. Thyroid. 1999;9(5):421-427.

4. Bilimoria KY, Bentrem DJ, Linn JG, et al. Utilization of total thyroidectomy for

papillary thyroid cancer in the United States. Surgery. 2007;142(6):906-913.

5. Mandel SJ, Mandel L. Radioactive iodine and the salivary glands. Thyroid. 2003;

13(3):265-271.

6. de Pedro Netto I, Fae A, Vartanian JG, et al. Voice and vocal self-assessment

after thyroidectomy. Head Neck. 2006;28(12):1106-1114.

7. Lombardi CP, Raffaelli M, D’Alatri L, et al. Voice and swallowing changes after

thyroidectomy in patients without inferior laryngeal nerve injuries. Surgery. 2006;

140(6):1026-1032.

8. Vartanian JG, Carvalho AL, Yueh B, et al. Long-term quality-of-life evaluation af-

ter head and neck cancer treatment in a developing country. Arch Otolaryngol

Head Neck Surg. 2004;130(10):1209-1213.

9. World Health Organization Quality of Life (WHOQOL) Group. Study protocol for

the World Health Organization project to develop a Quality of Life assessment

instrument (WHOQOL). Qual Life Res. 1993;2(153):9.

10. Crevenna R, Zettinig G, Keilani M, et al. Quality of life in patients with non-

metastatic differentiated thyroid cancer under thyroxine supplementation therapy.

Support Care Cancer. 2003;11(9):597-603.

11. Dagan T, Bedrin L, Horowitz Z, et al. Quality of life of well-differentiated thyroid

carcinoma patients. J Laryngol Otol. 2004;118(7):537-542.

12. Alexander C, Bader JB, Schaefer A, Finke C, Kirsch CM. Intermediate and long-

term side effects of high-dose radioiodine therapy for thyroid carcinoma. J Nucl

Med. 1998;39(9):1551-1554.

13. Malpani BL, Samuel AL, Ray S. Qualification of salivary gland function in thyroid

cancer patients treated with radioiodine. Int J Radiation Oncol Biol Phys. 1996;

35:535-540.

14. Newkirk KA, Ringel MD, Wartofsky L, Burman KD. The role of radioactive iodine

in salivary gland dysfunction. Ear Nose Throat J. 2000;79(6):460-468.

15. ASA Physical Status Classification. http://www.asahq.org/clinical/physicalstatus

.htm. Accessed July 10, 2008.

16. Vartanian JG, Carvalho AL, Yueh B, et al. Brazilian-Portuguese validation of the

University of Washington Quality of Life Questionnaire for patients with head and

neck cancer. Head Neck. 2006;28(12):1115-1121.

17. Gonc¸alves Filho J, Kowalski LP. Surgical complications after thyroid surgery per-

formed in a cancer hospital. Otolaryngol Head Neck Surg. 2005;132(3):490-

494.

18. Bushnell DL, Boles MA, Kaufman GE, Wadas MA, Barnes E. Complications, se-

quela and dosimetry of iodine-131 therapy for thyroid carcinoma. J Nucl Med.

1992;33(12):2214-2221.

19. Maier H, Bihl H. Effect of radioactive iodine therapy on parotid gland function.

Acta Otolaryngol. 1987;103(3-4):318-324.

20. Botella-Carretero JI, Gala´n JM, Sancho J, Escabar-Marreale HF. Quality of life

and psychometric functionality in patients with differentiated thyroid carcinoma.

Endocr Relat Cancer. 2003;10(4):601-610.

21. Chow SM, Au KH, Choy TS, et al. Health-related quality-of-life study in patients

with carcinoma of the thyroid after thyroxine withdraw for whole body scanning.

Laryngoscope. 2006;116(11):2060-2066.

22. Kung S, Rummans TA, Colligan RC, et al. Association of optimism-pessimism

with quality of life in patients with head and neck and thyroid cancers. Mayo Clin

Proc. 2006;81(12):1545-1552.

23. Tagay S, Herpertz S, Langkafel M, et al. Health-related quality of life, depression

and anxiety in thyroid cancer patients. Qual Life Res. 2006;15(4):695-703.

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 135 (NO. 4), APR 2009 WWW.ARCHOTO.COM

346

at Capes Consortia, on May 18, 2009 www.archoto.comDownloaded from

Livros Grátis
( http://www.livrosgratis.com.br )
 
Milhares de Livros para Download:
 
Baixar livros de Administração
Baixar livros de Agronomia
Baixar livros de Arquitetura
Baixar livros de Artes
Baixar livros de Astronomia
Baixar livros de Biologia Geral
Baixar livros de Ciência da Computação
Baixar livros de Ciência da Informação
Baixar livros de Ciência Política
Baixar livros de Ciências da Saúde
Baixar livros de Comunicação
Baixar livros do Conselho Nacional de Educação - CNE
Baixar livros de Defesa civil
Baixar livros de Direito
Baixar livros de Direitos humanos
Baixar livros de Economia
Baixar livros de Economia Doméstica
Baixar livros de Educação
Baixar livros de Educação - Trânsito
Baixar livros de Educação Física
Baixar livros de Engenharia Aeroespacial
Baixar livros de Farmácia
Baixar livros de Filosofia
Baixar livros de Física
Baixar livros de Geociências
Baixar livros de Geografia
Baixar livros de História
Baixar livros de Línguas

Baixar livros de Literatura
Baixar livros de Literatura de Cordel
Baixar livros de Literatura Infantil
Baixar livros de Matemática
Baixar livros de Medicina
Baixar livros de Medicina Veterinária
Baixar livros de Meio Ambiente
Baixar livros de Meteorologia
Baixar Monografias e TCC
Baixar livros Multidisciplinar
Baixar livros de Música
Baixar livros de Psicologia
Baixar livros de Química
Baixar livros de Saúde Coletiva
Baixar livros de Serviço Social
Baixar livros de Sociologia
Baixar livros de Teologia
Baixar livros de Trabalho
Baixar livros de Turismo
 
 