Tese de Doutoramento Medicina 2023 Faculdade de Ciências Médicas, Universidade NOVA de Lisboa

Liver surgery offers the most effective long-term oncological outcome for the treatment of metastatic liver disease (e.g. colorectal liver metastasis) and primary liver cancer (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 centres. 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 factor. 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 treatment. PVE was introduced decades ago by Japanese groups and is currently accepted as the standard of care for liver regenerative techniques due to its benefit in preventing postoperative liver failure and improving overall survival. 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 approach. 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 embolized. 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 regeneration. 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 groups, has robust liver regenerative results reported in animal and retrospective human studies. 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 Imaging. 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 agent. Beside NBCA-lipiodol, the other most frequent embolic material reported for PVE is a combination of polyvinyl alcohol (PVA) particles plus coils. 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 time and at a higher cost than PVE with NBCA plus Lipiodo. 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 Oncology. 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%. 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 Practice. 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 2021. 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 outcomes. 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 publication. 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 reported. Biembolization refers to concomitantly performing PVE and proximal hepatic vein embolization. LVD, reported as proximal hepatic vein embolization, as in biembolization, and distal hepatic vein embolization with concomitantly PVE, has encouraging liver hypertrophy results, superior to PVE. ALPPS, which stands for associating liver partition with portal vein ligation in staged hepatectomy, promotes robust and rapid liver regeneration but is associated with high morbidity and mortality. Our own group commented upon two recent publications regarding these future perspectives