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Biological and surgical determinants in the treatment of rectal cancer
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RESUMO: O cancro do recto é uma doença muito complexa que tem vindo a aumentar nas idades mais
jovens com um enorme impacto na qualidade de vida. Esta é uma patologia extremamente heterogénea no
que concerne ao seu comportamento, dependente de vários factores que determinam não só o seu curso
mas a resposta à terapêutica.
Nas últimas décadas progressos significativos têm sido feitos na abordagem do cancro do recto
devido a um melhor conhecimento da fisiopatologia da doença, conduzindo ao aparecimento de novas
opções de tratamento. De forma síncrona com uma evolução técnica, o conceito terapêutico também se
alterou, mudando de uma perspectiva exclusivamente focada nos outcomes oncológicos para um modelo
com preocupações relacionadas com os resultados funcionais e a qualidade de vida. O ênfase passou
também a residir na minimização dos efeitos deletérios do tratamento. Esta é a interrogação na base deste
trabalho: é possível encontrar determinantes biológicos e cirúrgicos do tratamento do cancro do
recto por forma a diminuir a morbilidade associada à terapêutica mas obtendo igualmente os
resultados pretendidos?
Existem vários factores biológicos que influenciam os resultados terapêuticos do cancro do recto
mas verifica-se, igualmente, um inquestionável impacto da opção cirúrgica selecionada. Sendo a nossa
meta a obtenção dos melhores resultados com a menor morbilidade, é necessário procurar estes
determinantes biológicos e cirúrgicos do tratamento óptimo.
O objectivo deste projeto é analisar possíveis determinantes da terapêutica do cancro do recto.
São colocadas as seguintes questões: 1) poderemos optimizar a seleção dos doentes para
quimioradioterapia neoadjuvante através da identificação de marcadores moleculares de resposta?, 2)
poderemos melhor selecionar a técnica cirúrgica nomeadamente com a excisão total do mesorecto via
transanal ou a excisão local em casos específicos? e 3) será possível uma melhor escolha dos doentes
para ileostomia derivativa através da identificação de factores preditivos de morbilidade associada a este
estoma?
A terapêutica neoadjuvante é atualmente administrada aos doentes com adenocarcinoma
localmente avançado do recto, maioritariamente com boa resposta tumoral. Contudo, cerca de um terço
dos doentes submetidos a quimioradioterapia não beneficiam deste tratamento, têm risco acrescido de
progressão de doença durante o mesmo bem como de toxicidade desnecessária. Até hoje, não foram
ainda validados quaisquer marcadores preditivos de resposta à quimioradioterapia que possam ajudar na
seleção dos doentes para esta terapêutica. Tendo em conta o seu papel na oncogénese do cancro do recto
bem como o seu envolvimento na resposta ao tratamento médico, colocámos a hipótese de os microRNAs
em particular microRNA-16, microRNA-21, microRNA-135b, microRNA-145 e o microRNA-335 poderem
ser biomarcadores de resposta à quimioradioterapia, predizendo os bons e os maus respondedores. Foi
encontrada uma associação estatisticamente significativa entre a sobre-expressão de microRNA-21 no
tecido tumoral pré- quimioradioterapia e pior resposta à mesma. Os nossos resultados sugerem a possibilidade do microRNAs-21 ser um biomarcador de resposta patológica à
quimioradioterapia no cancro do recto. A confirmação desta associação poderá ter uma translação para a
prática clínica corrente, com a inclusão do miRNA nos algoritmos de decisão terapêutica, possibilitando
uma melhor seleção dos candidatos a quimioradioterapia.
Durante os últimos 30 anos, grandes progressos cirúrgicos foram introduzidos no cancro do recto
com vista à melhoria dos outcomes e diminuição da morbilidade associada ao tratamento. O mais recente
avanço neste âmbito é a excisão total do mesorecto via transanal introduzida em 2010, com resultados a
curto prazo muito positivos. Contudo, os outcomes a longo prazo são ainda controversos. Analisámos os
outcomes oncológicos dos primeiros 50 doentes submetidos a esta técnica na nossa instituição e
procedemos à sua comparação com os obtidos por um grupo equiparado de doentes submetidos a excisão
total do mesorecto laparoscópica. Mesmo refletindo a curva de aprendizagem da nova técnica, foram
encontrados valores semelhantes entre os grupos no que concerne a sobrevivência global, sobrevivência
livre de doença e recidiva local a curto e longo prazo. Estes resultados apontam para que a excisão total do
mesorecto via transanal possa produzir outcomes oncológicos seguros, compatíveis com o que tem sido
publicado para a abordagem laparoscópica. Contudo, este estudo também enfatiza a sua exigente curva
de aprendizagem e o risco significativo de morbilidade que lhe está associado. Na realidade, qualquer que
seja a opção cirúrgica utilizada no tratamento do cancro do recto distal, é necessária elevada proficiência,
sendo que resultados óptimos só se atingem com treino adequado e auditoria contínua como garante da
sua melhoria à medida que a experiência aumenta.
Entendendo a excisão total do mesorecto como um dos grandes avanços no tratamento do cancro
do recto, não podemos deixar de reconhecer o seu impacto negativo na qualidade de vida dos doentes
com tumores distais. Neste contexto começaram a ser ponderadas estratégias terapêuticas menos
agressivas com vista a uma menor morbilidade, nomeadamente quimioradioterapia seguida de excisão
local. Através de uma revisão sistemática com metanálise que comparou, em contexto de neoadjuvância,
os outcomes da excisão local com os da cirurgia radical, encontrámos valores de recidiva local,
sobrevivência global e livre de doença semelhantes entre os grupos. Estes resultados podem ser
explicados pelo facto de o mais importante determinante oncológico não ser o estadiamento inicial mas sim
o pós quimioradioterapia, refletindo o comportamento biológico do tumor. No entanto, alguns estudos
incluídos nesta metanálise apenas mostraram o estadiamento inicial. Na realidade, após a
quimioradioterapia, a excisão local parece ser uma alternativa nos doentes com tumor restrito à submucosa
e sem adenopatias objectiváveis (ycT1N0), nos doentes com co-morbilidades ou que recusam cirurgia
radical.
Na cirurgia de excisão total do mesorecto é frequentemente realizada ileostomia derivativa por
forma a reduzir as consequências do leak anastomótico. Contudo, a maioria dos doentes não enfrenta esta
complicação sendo desnecessariamente exposta à potencial morbilidade do estoma. De facto, o efeito
protetor do estoma derivativo deve ser contrabalançado com a sua morbilidade, bastante relevante. Tendo
investigado marcadores de complicações associadas à ileostomia, identificámos a Diabetes Mellitus e a
morbilidade da cirurgia rectal índex como factores preditivos não só de maior morbilidade associada ao estoma e ao seu encerramento bem como de menor encerramento. Assim, quando ponderamos a
realização de uma ileostomia derivativa na cirurgia do recto, há que ter em conta a influência destes fatores
preditivos de morbilidade. É essencial individualizar as decisões terapêuticas e adoptar uma abordagem
mais seletiva no uso do estoma derivativo, especialmente nos doentes em que o risco do mesmo pode
superar as potenciais vantagens.
Em suma, existem vários factores que influenciam a conduta terapêutica na abordagem do cancro
do recto. Existem determinantes biológicos e cirúrgicos do tratamento desta doença que necessitam de ser
estudados, com vista ao atingir dos melhores resultados com a menor morbilidade. O papel dos
microRNAs na oncogénese é inquestionável como o é a influência de microRNAs específicos,
nomeadamente o microRNA-21, na resposta à quimioradioterapia neoadjuvante. Igualmente, também é
crítica a opção cirúrgica nos diferentes contextos clínicos. De facto, podemos individualizar as intervenções
cirúrgicas através do uso seletivo da excisão total do mesorecto via transanal nos tumores distais ou da
excisão local pós quimioradioterapia nos doentes de alto risco com boa resposta, confinada à submucosa.
Igualmente, antes da realização de cirurgia de excisão radical, é imperativo optimizar o status geral do
doente e controlar factores de risco modificáveis como a Diabetes Mellitus por forma a diminuir igualmente
a morbilidade associada ao estoma de proteção.
ABSTRACT:Rectal cancer (RC) is a very complex disease that has been increasing in younger patients, imposing a great impact in quality of life. It is an extremely heterogeneous pathology in what regards to behaviour, which is dependent of many factors that determine its course and response to treatment. In the past decades, significant progress has been made in the management of RC due to a better knowledge of disease pathophysiology and consequent development of new therapeutic options. Synchronously with the technical evolution, the concept of oncological treatment also changed, from a perspective exclusively focused on survival outcomes to a model involving concerns with functional results and quality of life. Emphasis changed to minimizing the deleterious effects of treatment. However, many rectal cancer patients are still submitted to medical therapies and surgical options without any benefit and that even add unjustified morbidity. This is the core question of this work: can we find biological and surgical determinants of RC treatment in order to decrease its related morbidity while achieving the intended outcomes? There are biological factors that influence clinical results and there is an undeniable impact of the surgical options we select. As our goal is obtaining the best possible outcomes minimizing morbidity, we must search for the biological and surgical determinants guidelining the optimal treatment. The aim of this project is to provide new insights to possible determinants of RC treatment. We ask the following questions: 1) can we better select patients for chemoradiotherapy through the identification of molecular predictors of response?, 2) can we individualize the surgical technique for each RC patient, using transanal total mesorectal excision or local excision in selected cases? and 3) can we improve assortment of patients for a derivative ileostomy identifying factors predictive of related morbidity? Neoadjuvant therapy is currently given to the majority of locally advanced rectal cancer with a majority of good tumour response. However, one third of patients that undergo chemoradiotherapy do not profit from this option, are at increased risk of disease progression and even unnecessary toxicity. So far, there are no validated predictors of response to chemoradiotherapy to aid in deciding whether the patient should or not undergo this therapy, avoiding related morbidity. Considering their role in rectal cancer oncogenesis and involvement in the response to medical therapies, we hypothesized that microRNAs (miRNAs or miRs), in particular microRNA-16, microRNA-21, microRNA-135b, microRNA-145 and microRNA-335 are biomarkers of response to neoadjuvant CRT, predicting good and bad responders. We found a statistically significant association of microRNA-21 overexpression in pre- chemoradiotherapy rectal cancer tissue and worse response. Our results suggest that microRNA-21 may, indeed, be a biomarker of pathological response in rectal cancer. Confirmation as such could translate into clinical application through the inclusion of the levels of microRNA-21 in algorithms of treatment decision, certainly allowing a better selection of candidates for chemoradiotherapy During the last 30 years, great surgical progress was introduced in RC treatment aiming to improve outcomes and diminishing the morbidity associated with treatment. The most recent of theses attempts is transanal total mesorectal excision, developed in 2010, which yielded very positive short-term results. However, long-term outcomes are still controversial and not clarified. We analysed the oncological outcomes of the learning curve of this technique at our institution and compared them to a matched cohort of patients submitted to the standard of care laparoscopic total mesorectal excision. Similar long-term results regarding local recurrence, overall survival and disease-free survival were found. These results point out to the fact that transanal total mesorectal excision can produce short and long-term oncological safe results, compatible to what has been published for the laparoscopic approach. However, this work also emphasized the demanding learning curve and significant risk for morbidity associated with this novel technique. The fact is that, whatever option is used to performed distal RC surgery, it requires advanced surgical skills and optimal results can only be achieved with adequate training and continuous evaluation of outcomes to ensure they improve as experience grows. Transanal total mesorectal excision does not intent to replace other established approaches to rectal surgery but to add new alternatives to address difficult cases. As we understand TME as one of the greatest revolutions of rectal cancer treatment we also acknowledge its negative impact on the quality of life of patients with distal tumours. In this setting, less aggressive therapeutic strategies started to be discussed in order to decrease therapeutic morbidity, namely neoadjuvant chemoradiotherapy combined with local excision. Through a systematic review and meta analysis that compared the outcomes of local excision and radical surgery in the post neoadjuvant setting, we found similar outcomes between groups in relation to local recurrence, overall survival and disease-free survival. These results are explained by the fact that the most relevant determinant of local recurrence and survival is not the baseline staging but the post chemoradiotherapy one, that reflects tumour biologic behaviour. However, some studies included in this metanalysis were based on initial staging. In sum, after CRT, patients with an incomplete response contained in the mucosa or submucosa with negative nodes (ycT1N0) may be an indication for LE. This strategy can also be considered in trial setting or as an option for patients refusing abdominoperineal resection or with significant comorbidity. Still in rectal cancer surgery, defunctioning ileostomy is frequently constructed to reduce the poor consequences of a leak. However, the majority of patients does not face anastomotic breakdown and is unnecessarily exposed to stoma potential complications. In fact, stoma protective effect needs to be balanced against its morbidity, which is actually quite high. We identified Diabetes Mellitus and complications of the index rectal surgery as predictive of higher ileostomy morbidity and of closure-related problems as well as lower ileostomy reversal. So, when deciding over diverting a colorectal or coloanal anastomosis, the influence of these predictive factors must be taken into account. It is essential to individualize treatment decisions and adopt a more selective approach concerning the use of a defunctioning ileostomy, especially for patients in which the risks of having a stoma may offset potential advantages. In summary, there are many factors influencing the proper therapeutic conduct to follow in the approach of rectal cancer. There are biological and surgical determinants of the treatment of this disease that need to be analysed, in order to achieve the best results with the lowest morbidity. The role of the microRNA in oncogenic pathways is undeniable as is the influence of specific microRNA, namely miR-21, in the response to chemoradiotherapy. Likewise, the choice of particular surgical interventions in different clinical settings can be critical to obtain the appropriate outcomes. We can individualize surgical options through the selective use of transanal total mesorectal excision in distal tumours or local excision in high risk patients with very good response, confined to the submucosa, in post neoadjuvant treatment. Likewise, prior to performing radical surgery, it is imperative to optimize patients and control modifiable risk factors as diabetes mellitus in order to decrease stoma-related morbidity.
ABSTRACT:Rectal cancer (RC) is a very complex disease that has been increasing in younger patients, imposing a great impact in quality of life. It is an extremely heterogeneous pathology in what regards to behaviour, which is dependent of many factors that determine its course and response to treatment. In the past decades, significant progress has been made in the management of RC due to a better knowledge of disease pathophysiology and consequent development of new therapeutic options. Synchronously with the technical evolution, the concept of oncological treatment also changed, from a perspective exclusively focused on survival outcomes to a model involving concerns with functional results and quality of life. Emphasis changed to minimizing the deleterious effects of treatment. However, many rectal cancer patients are still submitted to medical therapies and surgical options without any benefit and that even add unjustified morbidity. This is the core question of this work: can we find biological and surgical determinants of RC treatment in order to decrease its related morbidity while achieving the intended outcomes? There are biological factors that influence clinical results and there is an undeniable impact of the surgical options we select. As our goal is obtaining the best possible outcomes minimizing morbidity, we must search for the biological and surgical determinants guidelining the optimal treatment. The aim of this project is to provide new insights to possible determinants of RC treatment. We ask the following questions: 1) can we better select patients for chemoradiotherapy through the identification of molecular predictors of response?, 2) can we individualize the surgical technique for each RC patient, using transanal total mesorectal excision or local excision in selected cases? and 3) can we improve assortment of patients for a derivative ileostomy identifying factors predictive of related morbidity? Neoadjuvant therapy is currently given to the majority of locally advanced rectal cancer with a majority of good tumour response. However, one third of patients that undergo chemoradiotherapy do not profit from this option, are at increased risk of disease progression and even unnecessary toxicity. So far, there are no validated predictors of response to chemoradiotherapy to aid in deciding whether the patient should or not undergo this therapy, avoiding related morbidity. Considering their role in rectal cancer oncogenesis and involvement in the response to medical therapies, we hypothesized that microRNAs (miRNAs or miRs), in particular microRNA-16, microRNA-21, microRNA-135b, microRNA-145 and microRNA-335 are biomarkers of response to neoadjuvant CRT, predicting good and bad responders. We found a statistically significant association of microRNA-21 overexpression in pre- chemoradiotherapy rectal cancer tissue and worse response. Our results suggest that microRNA-21 may, indeed, be a biomarker of pathological response in rectal cancer. Confirmation as such could translate into clinical application through the inclusion of the levels of microRNA-21 in algorithms of treatment decision, certainly allowing a better selection of candidates for chemoradiotherapy During the last 30 years, great surgical progress was introduced in RC treatment aiming to improve outcomes and diminishing the morbidity associated with treatment. The most recent of theses attempts is transanal total mesorectal excision, developed in 2010, which yielded very positive short-term results. However, long-term outcomes are still controversial and not clarified. We analysed the oncological outcomes of the learning curve of this technique at our institution and compared them to a matched cohort of patients submitted to the standard of care laparoscopic total mesorectal excision. Similar long-term results regarding local recurrence, overall survival and disease-free survival were found. These results point out to the fact that transanal total mesorectal excision can produce short and long-term oncological safe results, compatible to what has been published for the laparoscopic approach. However, this work also emphasized the demanding learning curve and significant risk for morbidity associated with this novel technique. The fact is that, whatever option is used to performed distal RC surgery, it requires advanced surgical skills and optimal results can only be achieved with adequate training and continuous evaluation of outcomes to ensure they improve as experience grows. Transanal total mesorectal excision does not intent to replace other established approaches to rectal surgery but to add new alternatives to address difficult cases. As we understand TME as one of the greatest revolutions of rectal cancer treatment we also acknowledge its negative impact on the quality of life of patients with distal tumours. In this setting, less aggressive therapeutic strategies started to be discussed in order to decrease therapeutic morbidity, namely neoadjuvant chemoradiotherapy combined with local excision. Through a systematic review and meta analysis that compared the outcomes of local excision and radical surgery in the post neoadjuvant setting, we found similar outcomes between groups in relation to local recurrence, overall survival and disease-free survival. These results are explained by the fact that the most relevant determinant of local recurrence and survival is not the baseline staging but the post chemoradiotherapy one, that reflects tumour biologic behaviour. However, some studies included in this metanalysis were based on initial staging. In sum, after CRT, patients with an incomplete response contained in the mucosa or submucosa with negative nodes (ycT1N0) may be an indication for LE. This strategy can also be considered in trial setting or as an option for patients refusing abdominoperineal resection or with significant comorbidity. Still in rectal cancer surgery, defunctioning ileostomy is frequently constructed to reduce the poor consequences of a leak. However, the majority of patients does not face anastomotic breakdown and is unnecessarily exposed to stoma potential complications. In fact, stoma protective effect needs to be balanced against its morbidity, which is actually quite high. We identified Diabetes Mellitus and complications of the index rectal surgery as predictive of higher ileostomy morbidity and of closure-related problems as well as lower ileostomy reversal. So, when deciding over diverting a colorectal or coloanal anastomosis, the influence of these predictive factors must be taken into account. It is essential to individualize treatment decisions and adopt a more selective approach concerning the use of a defunctioning ileostomy, especially for patients in which the risks of having a stoma may offset potential advantages. In summary, there are many factors influencing the proper therapeutic conduct to follow in the approach of rectal cancer. There are biological and surgical determinants of the treatment of this disease that need to be analysed, in order to achieve the best results with the lowest morbidity. The role of the microRNA in oncogenic pathways is undeniable as is the influence of specific microRNA, namely miR-21, in the response to chemoradiotherapy. Likewise, the choice of particular surgical interventions in different clinical settings can be critical to obtain the appropriate outcomes. We can individualize surgical options through the selective use of transanal total mesorectal excision in distal tumours or local excision in high risk patients with very good response, confined to the submucosa, in post neoadjuvant treatment. Likewise, prior to performing radical surgery, it is imperative to optimize patients and control modifiable risk factors as diabetes mellitus in order to decrease stoma-related morbidity.
Descrição
Palavras-chave
Cancro do recto MicroRNAs MicroRNAs 21 Excisão total do mesorecto via transanal Excisão local Ileostomia Rectal cancer MicroRNAs MicroRNAs-21 Transanal total mesorectal excision Local, excision Ileostomy