BestFLR - RANDOMIZED CONTROLLED CLINICAL TRIAL COMPARING PREOPERATIVE PORTAL EMBOLIZATION
WITH POLYVINYL ALCOHOL PARTICLES (PVA) AND COILS VERSUS N-BUTYL CYANOACRYLATE (NBCA)
JOSÉ HUGO MENDES LUZ
A thesis submitted in partial fulfillment of the requirements for the Doctoral Degree in Medicine at Faculdade de Ciências Médicas | NOVA Medical School of NOVA University Lisbon
February 2022
BestFLR - RANDOMIZED CONTROLLED CLINICAL TRIAL COMPARING PREOPERATIVE PORTAL EMBOLIZATION WITH POLYVINYL ALCOHOL PARTICLES (PVA) AND COILS VERSUS N-BUTYL CYANOACRYLATE (NBCA)
Student’s name: José Hugo Mendes Luz Supervisor: Doutor Professor Tiago Campos Andrada de Faria Bilhim. Assistant Professor at NOVA Medical School / Faculdade de Ciências Médicas da Universidade NOVA de Lisboa.
A thesis submitted in partial fulfilment of the requirements for the Doctoral Degree in Medicine
February 2022
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Autor: JOSÉ HUGO MENDES LUZ
Tese para obtenção do grau de Doutor em Medicina na Faculdade de Ciências Médicas | NOVA Medical School da Universidade NOVA de Lisboa
Fevereiro 2022
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BestFLR - RANDOMIZED CONTROLLED CLINICAL TRIAL COMPARING PREOPERATIVE PORTAL EMBOLIZATION WITH POLYVINYL ALCOHOL PARTICLES (PVA) AND COILS VERSUS N-BUTYL CYANOACRYLATE (NBCA)
Autor: JOSÉ HUGO MENDES LUZ
Orientador: Doutor Professor Tiago Campos Andrada de Faria Bilhim. Professor auxiliar convidado da NOVA Medical School / Faculdade de Ciências Médicas da Universidade NOVA de Lisboa.
Tese para obtenção do grau de Doutor em Medicina na Faculdade de Ciências Médicas | NOVA Medical School da Universidade NOVA de Lisboa
Fevereiro 2022
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“A Vida é um momento, um sopro.
E a gente só leva daqui o Amor que deu e recebeu, a Alegria, o Carinho, e nada mais.”
Chico Xavier
“Don't ever let somebody tell you, you can't do something. Not even me.
People can’t do something themselves, they want to tell you that you can’t do it!”
Will Smith
Aos meus pais, Beatriz Vaz de Melo Mendes e Paulo Ribeiro Luz, por serem meu modelo, minha inspiração, meus maiores e incansáveis motivadores.
Gratidão. Eu amo vocês profundamente.
Aos meus filhos, presentes de Deus, João Vítor Neves Luz, Gabriela Neves Luz, Pedro Neves Luz e Toby, pelo apoio, carinho, compreensão nos momentos mais difíceis.
À minha esposa Flávia Neves, pelo apoio incondicional e entusiasmo e pelo amor de tantos anos.
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Acknowledgements
At the end of this Thesis, I would like to express my gratitude to those who have contributed to the accomplishment of this work and who have encouraged me throughout this journey.
To Professor Tiago Bilhim, I am truly thankful for accepting to be my Tutor, in a Thesis in the field of Portal Vein Embolization and Liver Surgery. I am also extremely grateful for his important role in integrating me in the clinical and research network at the Interventional Radiology Unit (URI) and Hepato-Biliary and Transplantation Center at Curry Cabral hospital.
Moreover, I express my gratitude for sharing with me all his knowledge about the difficulties and decisions in the writing and publishing process.
To Professor Paula Mendes Luz I do not have enough words to thank for her admirable patience and generosity and for all that she has taught me over these years. Ever since we started to work together in 2016, when I dared to invite her to tutor me in the conceptualization of a randomized controlled study, Paula has encouraged me to move forward. I am extremely grateful to her for believing in me, in my ideas and for becoming a member of our Team. I also thank Paula for her extreme care with every single detail of the entire project.
To Dr. Filipe Veloso Gomes for his restless enthusiasm, scientific insights, and true support in the most critical times, to Dra. Élia Coimbra for fully embracing this journey despite of not liking it or fully believing in the new PVE approach and to Dr. Nuno Vasco Costa for his ever- happy operating room mood, for his true interest in the project and incredible support.
To all my colleagues (medical doctors, nurses, radiographers, administrative staffs, researchers and so on) from Curry Cabral hospital and Centro Hospitalar Universitário Lisboa Central, whose list of names would not fit on this page, with whom it was a great pleasure to collaborate. Work with all of you made me a better interventional radiologist, a better researcher, and a better person. I really appreciate all the support, and, above all, I thank you all for your friendship.
Also, to all my colleagues and friends back in the National Institute of Cancer in Rio de Janeiro, Brazil. Even with the whole Atlantic Ocean between us it was always very good to feel their support and cheering. I am deeply grateful.
To my family and friends, for being always present, for praying for me, for celebrating with me the happy moments and each victory, and for encouraging me in the tough and difficult moments.
And at last, but certainly not least, an enormous gratitude to God.
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Publications
In accordance with “Artigo 34o do Decreto-Lei no 115/2013”, this Thesis contains materials and results from the following papers, which were published, accepted or submitted for publication. The author of this dissertation has contributed actively in the conceptualization, execution, interpretation and writing of these works.
Original Research:
1. Luz JHM, Luz PM, Bilhim T, et al. Portal vein embolization with n-butyl- cyanoacrylate through an ipsilateral approach before major hepatectomy: single center analysis of 50 consecutive patients. Cancer Imaging. Sep 2017;17(1):25.
doi:10.1186/s40644-017-0127-3
2. Camelo R, Luz JH, Gomes FV, Coimbra E, Costa NV, Bilhim T. Portal Vein Embolization with PVA and Coils before Major Hepatectomy: Single-Center Retrospective Analysis in Sixty-Four Patients. J Oncol. 2019;2019:4634309.
doi:10.1155/2019/4634309
3. Luz JHM, Veloso Gomes F, Costa NV, et al. BestFLR Trial: Liver Regeneration at CT before Major Hepatectomies for Liver Cancer-A Randomized Controlled Trial Comparing Portal Vein Embolization with
N -Butyl-Cyanoacrylate Plus Iodized Oil versus Polyvinyl Alcohol Particles Plus Coils. Radiology. Apr2021:204055. doi:10.1148/radiol.2021204055
Review Article:
4. Luz JH, Gomes FV, Coimbra E, Costa NV, Bilhim T. Preoperative Portal Vein Embolization in Hepatic Surgery:
A Review about the Embolic Materials and Their Effects on Liver Regeneration and Outcome. Review Article. Radiology Research and Practice. 21/02/2020 2020;2020:9. Article ID 9295852. doi:https://doi.org/10.1155/2020/9295852
Letter to the Editor / Commentary:
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doi:10.1016/j.surg.2020.03.004
6. Luz JHM, Bilhim T. Portal vein embolization, biembolization, and liver venous deprivation. Radiol Bras. 2021 May-Jun 2021;54(3):206-207.
doi:10.1590/0100-3984.2021.0040
7. Mendes Luz JH. Predictive Factors for Optimizing Liver Hypertrophy with
PVE Before Major Hepatectomies. Cardiovasc Intervent Radiol. Nov
2021;44(11):1847-1848. doi:10.1007/s00270-021-02918-x
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Liver surgery offers the most effective long-term oncological outcome for the treatment of metastatic liver disease1 (e.g. colorectal liver metastasis) and primary liver cancer2-4 (e.g.
Hepatocarcinoma, Cholangiocarcinoma). Furthermore, advancements in surgical techniques combined with better postoperative care have decreased hepatectomy mortality rates to around 4 to 3% in high-volume centres5,6. Unfortunately, approximately less than 25% of liver cancer patients are suited for surgical treatment, being the small size of the non-tumoral part of the liver - the future liver remnant (FLR) – the main limiting factor7,8. Techniques to increase the FLR, known as liver regenerative strategies such as portal vein embolization (PVE), will increase the FLR volume and consequently allow otherwise non-operable patients to undergo this potentially curative treatment9. PVE was introduced decades ago by Japanese groups10,11 and is currently accepted as the standard of care for liver regenerative techniques due to its benefit in preventing postoperative liver failure12-14 and improving overall survival14,15. The rationale of PVE is related to the occlusion of the portal vein branches that irrigate the tumoral liver and redirecting all portal flow to the contralateral side, the FLR. This process succumbs in the increase of the FLR after two to six weeks.
Technically PVE is commonly accomplished by a liver percutaneous approach16. First an ultrasound guided transhepatic access to the portal vein is obtained, followed by a vascular sheath being placed in the main portal vein. Through the catheterization of the portal vein using angiographic catheters and microcatheters the target portal vein branches are embolized17. Nearly all types of embolic materials have been tested and reported for PVE with no real consensus on which one would induce the greatest degree of liver regeneration18. No randomized controlled trial had been performed to directly compare different embolic materials to perform PVE. The need for a well-designed, prospective, and controlled study to address this gap in the oncological literature seemed necessary and defiant. N-Butyl- Cyanoacrylate (NBCA), a liquid embolic material, first used for PVE by French groups19, has robust liver regenerative results reported in animal20 and retrospective human studies21. Besides that, this liquid embolic has other potential advantages such as fast administration, low cost, and wide availability. At our own clinical practice there was an increasing perception of the distinct potential role of NBCA-Lipiodol for PVE, as to push us to look at our own results.
This resulted in our first publication which reported a cohort of 50 consecutive patients submitted to PVE with NBCA-lipiodol published in the journal Cancer Imaging22. The FLR increase (e.g., absolute liver hypertrophy) obtained at this retrospective analysis was 52%
at an average 4 weeks after PVE, which was similar to previous published results for PVE when adopting this liquid embolic agent23-26.
Beside NBCA-lipiodol, the other most frequent embolic material reported for PVE is a combination of polyvinyl alcohol (PVA) particles plus coils27-29. For this PVE approach PVA particles are injected first for distal embolization in the portal vein branches followed by the deposition of proximal coils for definitive obstruction. This approach has been the standard procedure for PVE in Curry Cabral hospital´s interventional radiology unit for more than a decade. Although an established technique, PVE with PVA particles plus coils seemed to promote less liver regeneration and associated with more contrast usage, more fluoroscopy
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time and at a higher cost than PVE with NBCA plus Lipiodol30,31. To change not only our practice but also to make scientific work useful to other centers our group decided to embrace an original, prospective project comparing NBCA-lipiodol and PVA particles plus coils for PVE before major hepatectomies, the BestFLR trial.
It also seemed reasonable and necessary to review and publish Curry Cabral interventional radiology unit experience with PVE using PVA particles plus coils. This retrospective analysis of data was published in the Journal of Oncology32. Once again, results from our own retrospective cohort were similar to previously reported FLR absolute hypertrophy results for PVE with PVA particles plus coils, ranging from 25 to 40%28,30.
We also noticed the necessity of performing an extensive review about PVE, more specifically the embolic materials reported for this procedure, their technical specifications, efficacy, complications, and clinical outcomes. This work was gathered as a detailed literature review of related publications up to August 2019 focusing on the results of each embolic agent and mixtures used for PVE, their handling, safety profiles, and liver hypertrophy regenerative results, also exemplifying with clinical cases from our own experience. This review article was published in the journal Radiology Research and Practice18.
As mentioned, to build up higher levels of evidence a randomized controlled trial (RCT) was necessary to address the difference between the two most commonly used embolic materials for PVE: NBCA-Lipiodol versus PVA particles plus coils. This RCT was carried out in Curry Cabral hospital and published in Radiology in April 202133. This trial showed that PVE with NBCA-Lipiodol produced greater absolute liver hypertrophy compared to PVA particles plus coils (46% versus 30% at 14 days, p < .001 and 57% versus 37% at 28 days, p < .001, respectively). Also, more participants in the NBCA plus Lipiodol group presented sufficient liver hypertrophy for surgery 2 weeks after PVE compared to the PVA particles plus coils group (87% vs 53%, respectively; p = .008). This latter finding meant that patients in the NBCA- Lipiodol group were ready for the planned hepatectomy earlier, which might reduce tumor progression while patients are waiting for the liver to regenerate.
Concurrently, in the beginning of the year of 2021, with the publication of the results from the BestFLR, two systematic reviews with meta-analysis regarding liver regeneration predictive factors for PVE were also reported. Ali et al investigated PVE accomplished with different embolic materials for effectiveness in inducing future FLR hypertrophy and other outcomes34. This review included 2896 patients from 51 different studies. Liver regeneration results and growth success rate were statistically superior for NBCA-Lipiodol when compared to PVA particles plus coils. Also, PVE with NBCA-Lipiodol promoted shorter procedures and reduced fluoroscopy time (p < .001), lower radiation exposure (p = .01), and lower material costs (p < .001) than PVA plus coils. The second systematic review with meta-analysis identified two predictive factors for accomplishing higher FLR hypertrophy results, and, once again, NBCA-Lipiodol was found to be superior to PVA plus coils in promoting liver regeneration (significant difference of degree of hypertrophy - DH in favor of NBCA-lipiodol).
Our own group was invited to write a commentary about this relevant publication35,36. Pointing out to future perspectives, new regenerative techniques need to be addressed. With PVE, although highly effective, up to 20% of patients will not undergo the planned hepatectomy, due mainly to liver tumor progression during the regeneration waiting period after PVE or insufficient FLR hypertrophy. To accelerate liver regeneration and overcome insufficient FLR hypertrophy after PVE different strategies, such as biembolization, liver venous deprivation (LVD) and associating liver partition and portal vein ligation (ALPPS) have been reported37-39. Biembolization refers to concomitantly performing PVE and proximal
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commented upon two recent publications regarding these future perspectives43,44.
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tratamento de doença hepática metastática1 (e.g. metástase hepática colorretal) e cancro primário do fígado2-4 (e.g. hepatocarcinoma, colangiocarcinoma). Além disso, os avanços nas técnicas cirúrgicas combinados com melhores cuidados pós-operatórios diminuíram as taxas de mortalidade da hepatectomia para cerca de 4 a 3% em centros de referência com elevado volume5,6. Infelizmente, aproximadamente menos de 25% dos pacientes com cancro do fígado estão aptos para tratamento cirúrgico, sendo o pequeno tamanho da parte não tumoral do fígado - o futuro remanescente hepático (FLR) - o principal fator limitante7,8. Técnicas para aumentar a FLR, conhecidas como estratégias regenerativas do fígado, como a embolização da veia porta (PVE), aumentarão o volume do FLR e, consequentemente, permitirão que pacientes não operáveis sejam submetidos a esse tratamento potencialmente curativo9. A PVE foi introduzida há décadas por grupos japoneses10,11 e atualmente é aceite como técnica de regeneração hepática de eleição devido ao seu benefício na prevenção da insuficiência hepática pós-operatória12-14 e na melhora da sobrevida global14,15. O racional da PVE está relacionado com a oclusão dos ramos da veia porta que irrigam o fígado tumoral e redirecionam todo o fluxo portal para o lado contralateral saudável, o FLR. Este processo leva ao aumento do FLR após duas a seis semanas.
Tecnicamente, a PVE é comumente realizada por abordagem hepática percutânea16. Primeiro é obtido acesso transhepático da veia porta guiado por ultrassonografia, seguido pelo posicionamento de bainha vascular na veia porta principal. Através da cateterização da veia porta com cateteres angiográficos e microcateteres, os ramos alvo da veia porta são embolizados17. Quase todos os tipos de materiais embólicos já foram testados e publicados para PVE sem um consenso real sobre qual induziria o maior grau de regeneração hepática18. Nenhum estudo controlado randomizado foi realizado para comparar diretamente diferentes materiais embólicos para realizar PVE. A necessidade de um estudo bem desenhado, prospectivo e controlado para suprir essa lacuna na literatura oncológica parecia necessária e desafiadora. O N-Butil-Cianoacrilato (NBCA), um material embólico líquido, usado pela primeira vez para PVE por grupos franceses19, tem resultados robustos de regeneração hepática relatados em animais20 e estudos retrospectivos em humanos21. Além disso, esse agente embólico líquido apresenta outras vantagens potenciais, como administração rápida, baixo custo e ampla disponibilidade. Na nossa própria prática clínica houve uma percepção crescente do papel potencial distinto do NBCA-Lipiodol para a realização da PVE, o que nos levou a olhar para os nossos próprios resultados.
Isso resultou na nossa primeira publicação, que relatou uma coorte de 50 doentes consecutivos submetidos a PVE com NBCA-Lipiodol publicado na revista Cancer Imaging22. O aumento de FLR (e.g. hipertrofia hepática absoluta) obtido nesta análise retrospectiva foi de 52% 4 semanas após PVE, o que foi semelhante aos resultados publicados anteriormente para PVE com esse mesmo agente embólico23-26.
Além do NBCA-Lipiodol, o outro material embólico mais frequentemente reportado para PVE é uma combinação de partículas de poliviníl álcool (PVA) mais Coils27-30. Para esta abordagem na PVE as partículas de PVA são injetadas primeiro para embolização distal nos ramos da veia porta seguida pela deposição de Coils proximais para obstrução proximal e definitiva. Esta abordagem tem sido o procedimento padrão para PVE na unidade de
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radiologia de intervenção do hospital Curry Cabral por mais de uma década. Apesar de ser uma técnica consagrada, a PVE com partículas de PVA parece estar associada a menor regeneração hepática e com maior uso de contraste iodado, maior tempo de fluoroscopia e custo mais elevado do que a PVE com NBCA-Lipiodol30,31. Para alterar não apenas nossa prática, mas também tornar o trabalho científico útil para outros centros, decidimos abraçar um projeto original e prospectivo comparando partículas de NBCA-Lipiodol versus partículas de PVA mais Coils para PVE antes de grandes hepatectomias, o ensaio clínico BestFLR.
Pareceu também plausível e necessário rever e publicar a experiência da nossa unidade de radiologia de intervenção do hospital Curry Cabral com PVE usando partículas de PVA mais Coils. Esta análise retrospectiva dos dados foi publicada no Journal of Oncology32. Mais uma vez, os resultados da nossa própria coorte retrospectiva foram semelhantes aos resultados de hipertrofia absoluta de FLR relatados anteriormente para PVE com partículas de PVA mais Coils, variando de 25 a 40%28.
Percebemos, também, a necessidade de realizar uma extensa revisão sobre a PVE, mais especificamente sobre os materiais de embolização relatados para este procedimento, suas especificações técnicas, eficácia, complicações e resultados clínicos. Este trabalho foi publicado como uma revisão detalhada da literatura de publicações relacionadas até agosto de 2019 com foco nos resultados de cada agente embólico usadas para PVE, sua utilização, perfis de segurança e resultados regenerativos de hipertrofia hepática, exemplificando também com casos clínicos de nossa própria experiência. Este artigo de revisão foi publicado na revista Radiology Research and Practice18.
Como mencionado, para construir níveis mais altos de evidência científica, um ensaio clínico randomizado (RCT) foi necessário para abordar a diferença entre os dois materiais embólicos mais usados para PVE: NBCA-Lipiodol versus partículas de PVA mais Coils. Este RCT foi realizado no hospital Curry Cabral e publicado na revista Radiology em abril de 202133. Este estudo mostrou que PVE com NBCA-Lipiodol produziu maior hipertrofia hepática absoluta em comparação com partículas de PVA mais Coils (46% versus 30% em 14 dias, p <
.001 e 57% versus 37% em 28 dias, p < .001, respectivamente). Além disso, mais participantes do grupo NBCA-Lipiodol apresentaram hipertrofia hepática suficiente para cirurgia 2 semanas após PVE em comparação com o grupo de partículas de PVA mais Coils (87% versus 53%, respectivamente; p = .008). Este último achado significou que os pacientes do grupo NBCA- Lipiodol estavam prontos para a hepatectomia planeada mais cedo, o que pode reduzir a progressão do tumor hepático enquanto os pacientes aguardam a regeneração do fígado.
Concomitantemente, no início do ano de 2021, com a publicação dos resultados do BestFLR, também foram relatadas duas revisões sistemáticas com meta-análise sobre fatores preditivos de regeneração hepática para PVE. Ali et al investigaram a PVE realizada com diferentes materiais embólicos quanto à eficácia na indução de hipertrofia do FLR e outros desfechos34. Esta revisão incluiu 2.896 pacientes de 51 estudos diferentes. Os resultados da regeneração hepática e a taxa de sucesso de crescimento foram estatisticamente superiores para NBCA-Lipiodol quando comparados com partículas de PVA mais Coils. Além disso, PVE com NBCA-Lipiodol teve menor tempo de procedimento e tempo de fluoroscopia (p < .001), menor exposição à radiação (p = 0,01) e menor custo do procedimento (p < .001) do que PVA mais Coils. A segunda revisão sistemática com meta-análise identificou dois fatores preditivos associados a maior hipertrofia do FLR e, mais uma vez, NBCA-Lipiodol foi superior ao PVA mais Coils na promoção da regeneração hepática (diferença significativa no DH, grau de hipertrofia hepática, em favor de NBCA-Lipiodol). Nosso próprio grupo foi convidado a escrever um comentário sobre esta relevante publicação35,36.
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insuficiente da FLR após PVE, diferentes estratégias, como biembolização, deprivação venosa hepática (LVD) e associação de partição hepática e ligadura de veia porta (ALPPS) foram relatadas37-39. Biembolização refere-se à realização concomitante de PVE e embolização proximal da veia hepática. A LVD, relatada como embolização proximal da veia hepática (como na biembolização) e embolização distal da veia hepática concomitante com PVE, tem resultados robustos de hipertrofia hepática, superiores a PVE40. ALPPS, que significa associar partição hepática com ligadura da veia porta em hepatectomias em dois tempos, promove uma regeneração hepática também potente e rápida, mas está associada a alta morbilidade e mortalidade41,42. Fomos convidados a comentar duas publicações recentes sobre essas perspectivas futuras43,44.
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List of Abbreviations
CONSORT - Consolidated Standards of Reporting Trials CT – Computed tomography
DH - Degree of hypertrophy DMSO - Dimethyl sulfoxide
EVOH - Ethylene Vinyl Alcohol Copolymer FLR – Future liver remnant
FLR-F - FLR function FLR-V - FLR volume
Gd-EOB-DTPA - gadolinium ethoxybenzyl-DTPA GGVOD, Grifka-Gianturco vascular occlusion device HCC – Hepatocellular carcinoma
IQR - Interquartile Ranges
ISGLS - International Study Group of Liver Surgery KGR – Kinetic Growth Rate
LVD - Liver Venous Deprivation MHV - middle hepatic vein MS - Microspheres
MR – Magnetic resonance NBCA – N-butyl-cyanoacrylate NR - Not reported
PFO - Patent Foramen Ovale
PHLF – Post-hepatectomy liver failure PVA – Polyvinyl alcohol
PVE – Portal vein embolization RCT – Randomized Controlled Trial
remnantRLE - mean relative enhancement of the future liver remnant SD – Standard Deviation
TSH - Two-Stage Hepatectomy VP - Vascular plug
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• Comissão de Ética da NMS|FCM-UNL (CEFCM)
• INFARMED – Autoridade Nacional do Medicamento e Produtos da Saúde
• Conselho de Administração do Centro Hospitalar Universitário Lisboa Central
• Comissão Nacional de Protecção de Dados (CNPD)
• Comissão de Ética para a Investigação Clínica (CEIC)
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Table of Contents
Chapter I - Introduction
1. The Clinical Scenario 3
1.2 Liver Surgery and post-hepatectomy liver failure 5 2. Liver Regeneration and history of Portal Vein Embolization 9 3. Evidence and indications for PVE before Major Hepatectomies 14 3.1 Volumetric parameters for liver regeneration 15
3.2 Indications for PVE by CT Volumetry 17
3.3 Functional evaluation for PVE and Liver Surgery 20
Chapter II - PVE Technique – A Review
4. Portal Vein Embolization – The Technique 25
4.1 Liver approach for PVE 25
4.2 The embolic materials 30
4.2.1 NBCA-Lipiodol 30
4.2.2 Absolute Alcohol (Ethanol) 33
4.2.3 PVA / Microspheres plus coils 36
4.2.4 Vascular Plugs 40
4.2.5 Other Embolic Agents 42
Chapter III - Rationale and Aims 5. Rationale
5.1 The Research Question 47
6. Aims
6.1 The Randomized Controlled Trial - BestFLR Trial 51
Chapter IV – Results
7. Portal vein embolization with n-butyl-cyanoacrylate through an ipsilateral approach before major hepatectomy: single center analysis of 50 consecutive patients.
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8. Portal Vein Embolization with PVA and Coils before Major Hepatectomy: Single- Center Retrospective Analysis in Sixty-Four Patients. 67
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Chapter V – Discussion and Conclusions 10. Discussion
10.1 Post-hepatectomy liver failure 92
10.2 The continuous search for the ideal embolic agent 94
10.3 NBCA-Lipiodol superiority 96
10.4 Future perspectives 101
11. Conclusions 110
References
References 114
Supplementary material 1
Copyright Licenses from Publishers 133
Supplementary material 2
BestFLR Protocol 151
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Chapter I - Introduction
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1 1.1 The Clinical Scenario
Liver can be primarily affected by cancer, as in primary liver tumors such as Hepatocellular carcinoma (HCC) and cholangiocarcinoma or be secondarily involved as metastatic disease.
Approximately 75% of liver metastasis come from adenocarcinomas, of which, almost 80%
come from the colorectal location45. More than 1.9 million new colorectal cancer (including anus) cases and 935,000 deaths were estimated to occur in 2020, representing about one in 10 cancer cases and deaths46. Overall, colorectal ranks third in terms of incidence, but second in terms of mortality. Likewise, colorectal cancer is the second most common cause of cancer death in the western world and up to 50% of patients diagnosed with the disease develop metastatic spread to the liver47-49. For colorectal liver metastasis hepatic resection offers improved survival and the only hope for cure, with a median 5-year survival rate of nearly 50%50-53. However, only 20 to 30% of patients with colorectal liver metastases are eligible for curative resection54,55.
Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide in 202046. This disease is the most common cancer in 11 geographically diverse countries in Eastern Asia (Mongolia), South-Eastern Asia (e.g., Thailand, Cambodia, and Viet Nam), and Northern and Western Africa (e.g., Egypt and Niger).
As in colorectal metastases, primary liver cancer is also best managed with hepatic resection.
HCC and cholangiocarcinoma are the two main types of primary liver cancer, representing over 95% of primary liver malignancies. HCC, the most common primary liver cancer, is also successfully treated with non-surgical treatment modalities such as percutaneous thermal ablation and liver transplantation2,56-59. Patients with cholangiocarcinoma, which represents 10–25% of all hepatobiliary malignancies60, will also have a better oncological outcome when hepatectomy is performed3,61. As seen in metastatic liver disease, only up to 20% of the patients with primary liver cancer will be surgically treated.
Most of the patients will not be fitted for surgery due to the small volume of normal (non-tumoral) liver, known as the future liver remnant (FLR)7,8,62. Increasing the volume and function of the FLR, as achieved by PVE, will permit liver resection in patients considered unfit for surgery (due to small FLR) and will also improve safety after major hepatectomies by reducing post-hepatectomy liver failure (PHLF). PVE will not only enable more patients to be submitted to hepatectomies62-64, but will also translate into better overall survival7,64-69. Likewise, the impact of increasing FLR with PVE and allowing these patients to undergo liver surgery can be clearly appreciated when their overall survival is confronted with patients who were declined for liver surgery32 (Figure 1).
Chapter I - Introduction
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Figure 1. Overall survival according to surgery. Accomplishment of the planned liver surgery was associated with better overall survival when compared to those patients in whom surgery was declined for primary and secondary liver cancer (p < 0.001). Reproduced with permission32
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failure
The liver consists of eight functional segments, which have their own hepatic arterial and portal venous supply, biliary drainage, and hepatic venous drainage. As major hepatic resections require transection of the hepatic parenchyma along the boundaries of these segments, understanding the hepatic segmental anatomy and the terminology used for hepatic resections is crucial for PVE68. Couinaud, whose classification system is likely the most commonly used worldwide, divided the liver into eight segments based on third-order portal vein branching70,71 (Figure 2). The definition of a Major hepatectomy is widely accepted as the removal of four or more liver segments, since removal of three liver segments is associated with lower risk of post-operative mortality, severe morbidity, overall morbidity and hepatic-related morbidity72 (Figure 3).
Figure 2. Illustration of the segmental anatomy of the liver based on the third-order portal vein branching (Couinaud’s classification system) and the portal vein and hepatic vein branches. IVC:
inferior vena cava and PV: portal vein. Reproduced with permission68.
Chapter I - Introduction
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Figure 3. Representative hepatic resections. (A) Right hepatectomy or right hemihepatectomy (resection of segments 5–8) and left hepatectomy or left hemihepatectomy (resection of segments 2–
4). (B) Right trisectionectomy or extended right hepatectomy (resection of segments 4–8) and left lateral sectionectomy or bisegmentectomy 2 and 3 (resection of segments 2 and 3). (C) Segmentectomy 6 (resection of segment 6). (D) Bisegmentectomy 5 and 6 (resection of segments 5 and 6). Reproduced with permission68.
After resection of colorectal liver metastasis high mortality (9%–15%) has been reported73,74 mainly due to liver failure secondary to insufficient FLR functional volume.
Essentially, large volume liver resections and a small FLR after hepatectomy have been directly correlated with the occurrence of post-hepatectomy liver failure (PHLF) and death62 and an insufficient FLR is the main cause of postoperative mortality75. Remnant liver volume is also widely considered the key factor in predicting complications after major hepatectomy72. Consequently, at present, the only absolute contraindication for hepatic resection is the impossibility to resect all tumoral tissue while not remaining adequate functional liver parenchyma. The definition of a major hepatectomy - resection of four or more liver segments72 – is critical since the extent of a hepatic resection is associated with increased morbidity. In patients undergoing right and extended right hepatectomies for colorectal liver metastases a greater operative morbidity and mortality with worse overall survival compared to all other liver resections for the same disease is expected76. Advances in perioperative management and surgical techniques have improved the safety and extended the indications for liver resection over the past 2 decades77,78. Nevertheless, the resulting small FLR volume and compromised liver function in these patients increase the risk for the development of PHLF. Despite the introduction of functional and imaging measures to assess preoperatively the size and function of the FLR79, PHLF remains a major concern and has been shown to be the predominant cause of hepatectomy-related mortality77,80.
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different studies across multiple institutions and countries86. This PHLF definition takes in consideration not only the two most important laboratorial criteria (serum bilirubin concentration and prothrombin time index) but also the clinical status of the patient. Authors in this publication define PHLF as a postoperatively acquired deterioration in the ability of the liver to maintain its synthetic, excretory, and detoxifying functions, characterized by an increased international normalized ratio and hyperbilirubinemia (according to the normal cut- off levels defined by the local laboratory) on or after postoperative day 5. Other obvious causes for the observed biochemical and clinical alterations such as biliary obstruction should be ruled out. Furthermore, authors categorized PHLF in three different clinical subtypes as follows: Grade A when the resulting abnormal laboratory parameters do not change the clinical management of the patient, grade B when there is a deviation from the regular clinical management but manageable without invasive treatment and grade C when patients requires invasive treatment86.
Although there is not a full agreement about the minimum amount of remnant liver to avoid PHLF after major hepatectomies, most reports advocate a minimum FLR ratio of 25%
for patients with normal liver parenchyma status and a FLR ratio of 35% to 45% in diseased liver, chemotherapy-associated liver injury, cholestatic disease, high grade steatosis and cirrhosis13,87-95.
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2 Liver Regeneration and the history of Portal Vein Embolization
Liver regeneration is not new to clinical practice or medical knowledge. Ancient Greeks seemed to have a glimpse in this regenerative capacity of the liver, as demonstrated in the famous painting of the Prometheus Bound by Peter Paul Rubens (Boston Museum of Fine Arts Exhibition, 1993). In this myth, Prometheus is a Titan who looked for and aided mankind. Zeus wanted to destroy man and withdrew their privilege of using fire. Prometheus immediately stole fire and gave it back to man. Zeus became extremely angry and banished Prometheus to Mount Caucasus to be tightened to a rock. During daytime a long-winged eagle would eat his immortal liver, which would regenerate and grow to its original size overnight. The reparative capacity of the organ allowed not only the recurrent eating by the eagle, but also for the psychic trauma imposed on Prometheus. The relation between the amount of tissue eaten by the eagle and the appropriate rate of recovery suggests, at the very least, that the ancient Greeks knew about hepatic regeneration96,97 (Figure 4).
Figure 4. (a) Prometheus Bound by Peter Paul Rubens (completed 1618) showing how the eagle (painted by Frans Snyder) manages to inflict maximum pain on the victim by placing its talons in the groin and near the eye. Reproduced with permission of the Philadelphia Museum of Art. (b) Laconic ceramic kylix (goblet) fashioned in Sparta in the early part of the 6th century BCE and attributed to the so-named Painter of Archesilas II. The decoration shows a bearded Atlas with knees bent under the weight he must support, and Prometheus, tied to a pole, being tortured perpetually by the giant Caucasian eagle that tore out and ate his liver each day. Reproduced with permission98.
a b
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Despite our antecedent’s knowledge, now we know that, after partial hepatectomy, the remaining part of the liver goes through a process that is actually better defined as a compensatory growth instead of regeneration99. Regeneration starts with the formation of a blastema at the cut surface (with dedifferentiated cells) which is very different from what happens in the liver in which the excised parts do not grow back. Rather, the remaining liver expands in mass to compensate for lost tissue. Thus, liver regeneration is technically a process of compensatory growth rather than regeneration. The process of liver volume restoration in humans is initiated by the replication of various types of intrahepatic cells, followed by an increase in cell size. In humans, replication of hepatocytes generally starts within 1 day after a major resection. After replication has been completed, growth, consisting of an increase in cell size, occurs over several additional days12. The initiation and synchronization of replication in different types of hepatic cells depend on the extent of the resection, tissue damage, or both100-102. In small liver resections the replication rate is low while after major hepatectomies up to 90% of the remaining hepatocytes appear to start replication. The mediators of liver compensatory growth are very similar from those involved in the process of acute inflammation. After resection quiescent hepatocytes (G0) will enter G1 and S phases (Figure 5).
Figure 5. Pathways of Liver Regeneration Initiated by Major Hepatectomy.
After hepatectomy, nonparenchymal cells, such as stellate cells, Kupffer cells, leukocytes, and platelets, are activated by soluble factors, such as vascular endothelial growth factor and lipopolysaccharide. Interaction between activated vascular components, including platelets, leukocytes, sinusoidal endothelial cells, and Kupffer cells, results in the release of tumor necrosis factor α, interleukin-6, and serotonin. The cytokines cause a priming of the remnant hepatocytes, and concurrently, extracellular proteases such as urokinase-type plasminogen activator convert inactive hepatocyte growth factor to its active form. Inactive hepatocyte growth factor, which is secreted by
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factor β blocks further replication. The metabolic load resulting from the loss of hepatocytes is indicated by the accumulation of bile acids in the blood. The bile acids enter the hepatocytes and drive bile acid receptors such as the farnesoid X receptor, resulting in increased protein and DNA synthesis.
Reproduced with permission from Clavien et al12, Copyright Massachusetts Medical Society.
Platelets (thrombocytes) and bile acids were shown to be critically involved in liver regeneration103,104. Serotonin, a neurotransmitter transported by platelets, appears to be a co-mitogen, essential for hepatic regeneration. When bile-acid pools are high, regeneration is complete, whereas low bile flow is associated with reduced hepatocyte replication. This latter mechanism seems to be decisive in integrating the metabolic load of the liver and may have a direct effect on regeneration104.
Sir James Cantlie in his 1897 publication noted during an autopsy of a patient with a right liver lobe abscess, a hypertrophied left liver lobe due to the obliteration of the right portal vein105,106. He noted that the transition of the atrophied and hypertrophied part defined the anatomical midline of the liver, according to the portal blood supply division. This landmark, which connects the gallbladder fundus to the inferior vena cava, is known as the Cantlie's line. In 1920 investigators from the Rockefeller Institute for Medical Research tested the hypothesis of contralateral liver regeneration after the occlusion of portal branches from the other part of a rabbit´s liver107. They observed that it led to progressive and ultimately complete atrophy of the parenchyma in the region deprived of portal blood, and to hypertrophy of the rest of the hepatic tissue which receives such blood in excess (Figure 6).
Figure 6. Normal Liver Anatomy and the Principle of Portal-Vein Occlusion.
Panel A shows normal liver anatomy, with segments II through VIII shown. Segment I, which lies posteriorly, next to the vena cava, is not shown. The portal vein is shown, with the right portal vein, the left portal vein, and the left medial branch to segment IV. Panel B shows occlusion of the right portal vein, which results in ipsilateral atrophy of the right hemiliver (segments V through VIII) and
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contralateral compensatory hypertrophy of the left hemiliver segments I through IV. Reproduced with permission from Clavien et al12, Copyright Massachusetts Medical Society.
After two months they observed that the portal deprived part of the liver reduced to a fibrous remnant, while the remaining portal perfused liver achieved the volume of the entire original organ. The observed atrophy was simple, without any obvious degenerative changes. In 1975, Honjo et al. [1] reported portal vein ligation (PVL) as a treatment for unresectable liver cancer.
However, in their series, the effect of PVL was unclear because histologic examination of the affected cancer was not done. PVL required laparotomy.
The main goal of portal vein embolization (PVE) is to selectively induce FLR growth during the preoperative time course. This is achieved by embolization of portal branches of the future resected liver, where the primary or secondary liver tumor is located. This will lead to the redistribution of all portal blood flow, containing hepatotrophic factors, exclusively to the FLR. This technique was first applied in 1986 by the Japanese group from the Osaka University Medical School, published by Kinoshita et al108, in HCC patients with the objective of preventing spread of the intraportal tumor. Although authors used PVE to strengthen the anticancer effects of transarterial chemoembolization in HCC, all 21 patients demonstrated significant increase of the non-tumoral liver, the FLR109. With this work it was possible to conclude that PVE causes liver regeneration and this effect might be helpful for patients that needed to undergo major hepatectomies.
A few years later, in 1990, PVE was proposed by Makuuchi et al in patients with hilar cholangiocarcinoma carcinoma that frequently require major hepatectomy in relation to the tumor location110. Authors showed that PVE did not produce major side effects or significant increases of serum transaminase or bilirubin and enabled patients to undergo extensive liver resection with a low PHLF occurrence. Their rationale for using PVE was to minimize the abrupt increase in portal vein pressure at resection that can lead to hepatocellular damage to the FLR. They also intended to improve overall tolerance to major hepatectomy by increasing the liver mass before resection17. Two years later, in 1992, investigators from Gustave Roussy´s Interventional Radiology and Surgery department, in France, also published the benefits of performing preoperative PVE. They pointed out the importance of performing CT volumetry when planning liver resection demonstrating the role of performing PVE when the estimated FLR was less than 40% to avoid PHLF92. Since then, many centers reported their experience in adopting PVE in the liver preoperative scenario, enabling patients with small FLRs to be submitted to major hepatic resections.
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3 Evidence and Indications for PVE before Major Hepatectomies
After major hepatectomies the main cause of morbidity and mortality is the occurrence of PHLF. The smaller the FLR after surgery, higher the incidence of PHLF. Two decades ago, Abdalla et al64 compared the outcomes of patients submitted to extended liver resections with and without preoperative PVE. When the FLR was 20% or less, complications occurred in 50% of the patients while if the FLR was above that limit, complications occurred in only 13% of the patients (p = 0.02)64. Also, in this study, 18 extended right hepatectomies, with no PHLF, were performed following FLR growth induced by PVE. From this work, authors concluded that PVE enabled extensive hepatic resections in initially non-surgical or high-risk patients. Clearly, morbidity and mortality were more associated to the remaining liver volume after surgery (e.g., FLR) rather than the volume of liver resected during hepatectomy111. In primary and secondary hepatic malignancies, the oncological outcome is associated with the removal of all liver tumor, but clinical outcome is related to the volume and quality of the FLR.
Liver resection with preoperative PVE provide excellent oncological outcomes. Early studies from Europe showed 5-year overall survival of nearly 40% following resection of colorectal liver metastasis after PVE. These cohorts were composed of patients considered unresectable without PVE, with equivalent survival results when compared to patients that were “up-front”
surgical candidates67. There is substantial evidence for adopting PVE in the preoperative scenario of primary and secondary liver cancer. PVE has shown to reduce the risk of PHLF after major hepatectomies and increase the number of resectable patients64,112,113.
Indications for PVE are mainly related to the extent of the planned hepatectomy, the quality of the liver parenchyma and the FLR volume. For decades CT is used to make volumetric measurements of the total liver, the part of the liver to be resected, the tumor volume and the FLR21. Also, reports have shown that CT volumetry yields good measurements of CT volumes of hemihepatectomy specimens when compared to actual specimens’ volumes and weights114. Some minimal differences have been reported and they might reflect the fact that blood filled liver, included in the CT volumes, is usually excluded in the intraoperatively measured volumes. (Figure 7).
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Figure 7. Results of the regression analyses of intraoperative volumes and CT volumes showing good correlation. Reproduced with permission114.
3.1 Volumetric parameters for liver regeneration
There are two different ways to calculate liver volumes. Frequently authors use direct measurements of liver volumes to calculate the FLR, delineating the liver, tumors and FLR contours with semi-automatic softwares115 (Figure 8), using the following formula35:
FLR% = FLR volume divided by the total functional liver volume x 100%
(Functional liver volume = Total liver volume - tumor volume)
The other method of estimating liver volumes is related to the body surface116,117. This concept of the total estimated liver volume is based on the observation that in adults, without liver disease, liver volume correlates linearly with body size and weight118. For instance, in living donor liver transplantation, the patient's body weight is used to calculate the donor graft volume119. The formula to calculate the total estimated liver volume was established as120:
Total estimated liver volume = - 794 + 1267 x BSA
Of notice, this formula was derived and corroborated by studies of the Western population121,122.
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To measure liver growth on CT different volumetric parameters have been used and published. The main markers are absolute FLR growth, degree of hypertrophy (DH) and kinetic growth rate (KGR). Absolute FLR growth translates the FLR volume increase in relation to its original volume. For example, if patient´s FLR volume initially was 300ml and after PVE 450ml then the absolute FLR growth is 50%. As for DH it describes the increase in the FLR ratio after PVE. If patient´s FLR ratio increased from 20% to 30% after PVE then DH is 10%. KGR is a dynamic type of volumetric assessment. It calculates the DH over days or weeks, from the PVE date up to the CT imaging date after PVE, being commonly published as “% per week”.
Here is a summary of the volumetric parameters used to evaluate PVE effect:
● FLR Absolute growth:
○ (FLR volume after PVE - FLR initial volume / FLR initial volume) x 100%
○ example: (450 - 300 / 300) x 100% = 50%
● Degree of Hypertrophy (DH):
○ FLR ratio after PVE - FLR ratio initially
○ example: 30% - 20% = 10%
● Kinetic Growth Rate (KGR) peer week:
○ DH / number of weeks from PVE to the CT imaging after PVE
○ example: 10 / 4 = 2% per week
As the techniques and indications for PVE have evolved over time, numerous groups have attempted to more accurately predict postoperative outcomes on the basis of PVE- induced imaging volume changes110. Absolute hypertrophy has the advantage of directly measuring the capacity of the FLR to regenerate. Low values for absolute hypertrophy after PVE are associated with PHLF67,93,148. Also, absolute hypertrophy is not influenced by the atrophy of the non-FLR parenchyma as the FLR ratio (and DH) is, which might lead to a false interpretation of significant hypertrophy if only DH is taken into account130. Nevertheless, the FLR ratio, and its increase after PVE (e.g., DH) has traditionally been used as one of the main parameters for decision making in liver surgery1,3,9. DH, as KGR, is a good predictor of PHLF13. KGR is a dynamic volumetric tool, as it can be measured at any time point after PVE. For DH, it is necessary many weeks for it to become apparent (e.g., if measured too early the increase will be minimum). KGR is an early marker of the regenerative capacity of the FLR and may provide additional functional information beyond traditional, static measures of volume.
Shindoh et al showed that KGR has a better predictive value than degree of hypertrophy alone for postoperative outcomes243. Leung et al found similar results, depicting that KGR as well as the extent of growth correlated with PHLF. However, this latter study found that DH was a superior predictor for high-grade complications when compared to KGR13. Nonetheless, KGR rate is still a very useful index, since it is an early marker that may support going forward with the hepatic resection before the customary 4 to 6 weeks after PVE. Besides, in the study by Shindoh et all, patients that achieved a KGR above 2.0 did not presented any signs of PHLF, while 21.6% of patients with KGR bellow this value presented PHLF (p < 0.001). Also, in a comparison of the diagnostic capacity of standardized FLR volume, DH and KGR, of these variables, KGR <2.0% per week showed the highest accuracy (81%), with sensitivity of 100%
and specificity of 71% in predicting PHLF.
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Commonly groups report the use of preoperative PVE when the FLR ratio is less than 25% in patients with normal livers or 30% to 35% in chemotherapy heavily pre-treated patients and 40% in diseased liver (i.e.; cholestatic liver disease, liver fibrosis and cirrhosis)25,62,64,66,93,94,112,125-128 (Figure 8).
Figure 8. Segmentation process in a patient planned for right hemihepatectomy without resection of the middle hepatic vein (MHV) due to colorectal metastases a) Plain axial CT image shows a hypoattenuated metastasis in liver segment 8 (black arrows). b) and c) Detection of the liver outline.
Further metastases are depicted at the level of the proximal MHV in c) (black arrows). d) – f) Detection of the intrahepatic portal vein (in pink) and hepatic vein (in blue). g) – h) Definition of the transection plane (in red). Reproduced with permission114.
Nevertheless, patients with liver cirrhosis will show slower and inferior hepatic regeneration when compared to non-cirrhotic cohorts129 and PVE in cirrhotic patients will be used more liberally. Also in this scenario, a recent publication from Japanese and French groups showed that transarterial chemoembolization (TACE) followed by PVE is more effective than PVE alone130. Interestingly this study showed that not only TACE followed by PVE induces greater hypertrophy than PVE alone (in line with other publications131-133), but
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also the overall survival and progression free survival were consistently better in the TACE plus PVE group (60% versus 20% for overall survival at 3 years, p = .01 and 35% versus 0% for progression free survival at 3 years, p < .001) (Figure 9). As for PVE indications, this group uses PVE systematically before right hepatectomies for patients with livers containing severe fibrosis or cirrhosis even if the FLR% ratio is greater than 40%.
Figure 9. Kaplan-Meier survival curves: TACE plus PVE (TACE +) versus PVE alone. (A) Overall survival of patients with PVE alone versus patients with TACE plus PVE. (B) Progression-free survival of patients with PVE alone versus patients with TACE plus PVE. Reproduced with permission130.
Regarding Biliary cancer some crucial differences also influence the indications for PVE. Hepatectomy is complex, accompanied by caudate lobectomy, extrahepatic bile duct resection with bilioenteric anastomosis, portal vein resection and even pancreatoduodenectomy64,134,135. In a large study from Nagoya University 393 patients with biliary cancer were treated from 1991 to 2005. Of these, 279 patients (71%) were submitted to PVE, which accounts for more than two thirds of the total bulk of patients. One of the reasons for the frequent use of PVE is that even patients with FLR > 40%, but with low functional reserve (i.e., plasma disappearance rate of indocyanine green of the FLR < 0.05), were submitted to PVE. In this report patients with small FLR submitted to PVE showed similar survival rate when compared to those patients who underwent a less than 50% resection of the liver without PVE (4.5% versus 3.7%)134. Figure 10 exemplifies a decision diagram regarding major hepatectomies and the use of PVE as a preoperative procedure.
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Figure 10: Proposed Decision Tree for Major Hepatectomy in Patients with Normal Liver Parenchyma and Those with Cirrhosis. The cutoff points of 30% volume (Panel A) and 50% volume (Panel B) for the potential liver remnant are based on our current practice and available data. For cirrhotic livers with a rate of retention of indocyanine green (ICG) that is less than 14% at 15 minutes (Panel B) and livers with underlying noncirrhotic diseases such as steatosis or fibrosis, we apply the algorithm for normal liver parenchyma with a higher cutoff point (35 to 40%) for the volume of the potential liver remnant. Reproduced with permission from Clavien et al12, Copyright Massachusetts Medical Society.
3.3 Functional evaluation for PVE and Liver Surgery
Even though CT volumetry has been extensively used and reported as a central tool for decision making about indicating or not preoperative PVE, volume does not always reflect liver function136,137. Patients with sufficient FLR volume with or without adjuvant PVE still suffer PHLF. Recent studies evaluating liver volume and function gain after associating liver partition and portal vein ligation (ALPPS) have demonstrated that liver function increases only half-fold compared to volume gain138,139. After the first stage of ALPPS, the FLR volume increase significantly exceeded the functional gain, where the FLR increased 57% and the FLR function increased only 28% (p = .021). This extreme increase in FLR volume might not mean true hypertrophy, as edema due to venous congestion might play an important role, and FLR volume seems to overestimate FLR function after stage 1 of the ALPPS procedure140,141. Continuum research has shown that liver volume measurement alone does not appear to be the only definitive determination whether to proceed safely to liver surgery142. FLR function is as important as its volume estimation. Liver function can be evaluated by nuclear medicine (i.e. Galactosyl143-145 and 99mTc-mebrofenin hepatobiliary scintigraphy82,146,147), indocyanine green retention test148-150 and gadoxetic acid-enhanced magnetic resonance imaging151-153.
99mTc-mebrofenin hepatobiliary scintigraphy is highly predictable of PHLF, with a negative predictive value of 94% when a minimum cut-off value of 8.5%/min is not reached146,154. Similarly, liver function can be estimated by gadoxetic acid-enhanced magnetic resonance imaging (MRI) before and after PVE152,155. Indocyanine green retention, a simple and low-cost test, is also an option for liver function evaluation and has been used for decades for predicting PHLF before major hepatectomies and liver transplant18,156. Due to the inability of CT volumetry to evaluate liver parenchyma quality, the reported discrepancies between liver volume and function and the high capacity of current available liver function tests, CT volumetry should be at least complemented by functional liver evaluation before major hepatectomies (Figure 11).
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Figure 11. Reproduced with permission from Clavien et al12, Copyright Massachusetts Medical Society.
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Chapter II
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PVE Technique – A Review
Chapter II – PVE Technique – A Review
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Portal Vein Embolization The Technique
Different liver approaches, embolic materials, portal vein branches targeted, preprocedural planning, outcome evaluations and additional liver regenerative strategies for PVE have been tested and reported18,22,32,33,68,126,157-162.
4.1 Liver approach for PVE
Access to the portal vein system may be performed from different pathways. Several
techniques have been reported, including intraoperative portal branch ligation163,164, transileocolic PVE165, trans-splenic PVE166, transjugular PVE167, and transhepatic ipsilateral22,168 or transhepatic contralateral PVE23,169. Transileocolic access is a surgical procedure that is performed in the operating room under general anesthesia. An incision is made at the McBurney’s point and a trocar is introduced. When no unexpected findings and no dissemination is identified by laparoscopy, an additional incision is made, and a wound protector is applied. The ileocecal valve is exteriorized, and an ileocecal vein is dissected and punctured with a 7 French sheath to access and catheterize the mesenteric-portal venous system. For this technique authors usually use multipurpose catheters with balloon for embolization. An advantage of this type of approach is the possibility of laparoscopic inspection to be performed to avoid unnecessary PVE for patients with peritoneal dissemination165. A meta-analysis published in 2008 which examined the outcome of 1088 patients after PVE demonstrated that the FLR volume increase was significantly higher in patients who underwent PVE using a percutaneous approach (11.9%), compared with those patients who underwent PVE using the transileocolic approach (9.7%)113. Moreover, this surgical procedure has generally been replaced by the less invasive percutaneous techniques, which are accomplished using ultrasound-guided transhepatic punctures and mild conscious sedation.
As utilized in the TIPS procedure, the transjugular approach to PVE has been reported by Chinese investigators167 (Figure 12). Authors performed transjugular PVE in 18 patients with 100% of technical success. Compared with the liver percutaneous approach, the transjugular via might be associated with reduced bleeding risk. Also, it does not offer damage risk to the FLR during portal vein access as it occurs in the contralateral transhepatic approach17. Nevertheless, the transjugular PVE has been very scarcely reported and results from previous publication were not reproduced from different centers. The trans-splenic rout is the approach which has the advantage of not performing a liver puncture (Figure 13). The
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first publications for trans-splenic access reported the use of thicker needles (18 gauge) with contrast agent not always being injected in the intravascular territory as it often was performed by the injection into the splenic pulp for splenoportography170. A decade later, another report described the use of fine-needle puncture (22-gauge) to permit trans-splenic interventions171. Since then, numerous studies have described percutaneous trans-splenic portal vein access, primarily as a route for treating cirrhotic and non-cirrhotic portal vein occlusions with TIPS172,173 or portal vein stenting and variceal embolization in patients with intrahepatic portal vein thrombosis174,175.
Figure 12: Transjugular approach for performing PVE. (a) Portography through a transjugular approach immediately before PVE. (b) Portography shows the occlusion of the right portal vein with continued patency of the veins supplying the left lateral liver. Reproduced with permission167.
a b
a b
