Masterclass 5 - Liver Transplant Oncology

Background
Living donor liver transplantation is one of the most complex operations in surgery. It demands skills and dexterity as well as thorough multi-facet knowledge in physiology, anatomy, hepatology and oncology from surgeons. Since the inception of living donor liver transplantation almost three decades ago, there has been substantial improvements and refinements in the operative techniques leading to standardization of the procedure. As such, some of the transplant knowledge and skills has been extrapolated to complex liver resection(CLR) of locally advanced hepatobiliary cancer but it remained uncertain if such knowledge and skills transferal has any impact on the postoperative outcome of CLR.
Methods
Postoperative outcome after CLR between 1995 and 2019 were reviewed and correlated with LT experience in a single center with both LT and CLR service. CLR was defined as hepatectomy with vasculobiliary reconstruction, or multivisceral resection, central bisectionectomy (S4/5/8), or associating liver partition and portal vein ligation for staged hepatectomy. Spearman rank correlation and receiver operating characteristic analysis were
used to define the association between CLR-related outcomes and LT experience.
Results
With cumulative single-center experience of 1452 LT, 222 CLR were performed during the study period [hepatectomy with biliary (27.0%), or vascular (21.2%) reconstruction, with multivisceral resections (9.9%), with associating liver partition and portal vein ligation for staged hepatectomy (18.5%)] mainly for hepatocellular carcinoma (53.2%), and hilar cholangiocarcinoma (14%). Median tumor size was 7.0 cm. Other features include
macrovascular invasion (23.4%), and juxta-visceral invasion (14%). Major postoperative complication rate was 25.2% and mortality rate was 6.3%. CLR-complication rate was inversely associated with LT experience (R =0.88, P 0.005). Receiver operator characteristic analysis revealed the cutoff for LT experience to have the greatest influence on CLR was 95 with a sensitivity of 100% and Youden index of 1. Multivariable analysis showed that bloo transfusion, prolonged operating time, LT experience < /.95 were associated with major postoperative complications.
Conclusion
LT experience was complimentary to CLR for locally advanced hepatobiliary malignancy with improved postoperative outcome.

Metastatic cancer has been a feared disease due to the short survival after diagnosis and the lack of effective therapy. Surgery, Radiation therapy and Cytotoxic Chemotherapy had been the milestones of treatment developed up to the end of the 19th century. Unfortunately, with a few exceptional types like Germ Cell Tumors, most metastatic cancer patients will not outlive their disease. As we entered the 20 th century, we have made many important discoveries like cancer causing genes and we developed specific targeted inhibitors to correct these biological aberrations. The successful development of Immune Checkpoint inhibitors (ICI) in 2009 had been the start of a revolution for metastatic cancer treatment. Over the past decade, many different types of metastatic cancers were successfully treated and patients achieved long term durable remissions from their deadly diagnosis. Initially these were achieved with ICI alone, more recently, therapy evolved to ICI combinations, ICI combined with targeted therapy and ICI combined with chemotherapy. The current state of the art for ICI based therapy for metastatic cancers will be reviewed. 
Patients who have received a transplanted organ are particularly prone to develop cancers due to the use of immune-suppressive therapy to prevent graft rejection. Are they candidates for ICI based therapy? The current limitations for using ICI in transplant related malignancy will be discussed and early successful adaption of ICI will be presented.

Liver transplant is the best treatment option for selected early stage hepatocellular carcinoma (HCC) patients. Given the shortage of organs with increasing time on the waitlist, it is recommended that local regional therapy be applied if the anticipated waiting time is longer than 6 months. 


Local regional therapy has been widely used as a bridge to transplant, aiming to reduce tumor progression and waitlist dropout. The response to local regional therapy also predicts post-transplant recurrence and is an important tool to select biologically favorable HCC for transplant. 


The ideal bridging therapy should be safe, non-invasive and effective. Various local regional therapies including transarterial chemoembolization (TACE), radiofrequency ablation (RFA), high intensity focused ultrasound (HIFU) and selective internal radiation therapy (SIRT) have been studied extensively. Recently, our team has pioneered the use of stereotactic body radiation therapy (SBRT) as bridging therapy. We have demonstrated SBRT offered better tumor control at 1-year and reduced the risk of waitlist dropout. Since then, SBRT has replaced other local regional therapy as the 1st line bridging therapy for HCC waitlist candidates. 

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. According to Hong Kong Cancer Registry, liver cancer ranks the fifth in incidence and the third in cancer-related mortality in 2020. Liver transplantation (LT) is the best treatment option as total hepatectomy eliminates detectable and undetectable tumor lesions as well as the cirrhotic liver due to underlying liver disease. But since few liver transplant donors are available, meticulous selection of patients to minimize the recurrence and optimize long-term survival are crucial.


The Milan criteria (single tumor 5cm, or up to three tumors 3cm have been the gold stndard for selecting patients with HCC for LT for over the two decades. Since then, patient’s eligibility for LT continued to evolve; one attractive strategy is the application of locoregional treatment (LRT) to downstage patients whose tumor burden exceeding the established limits to within the Milan Criteria. One of the commonly used criteria is the University of California, San Francisco downstaging (UCSF-DS) criteria. Several large-scale studies showed that patients with successful downstaging after LT had similar outcomes to patients with HCC initially meeting the Milan criteria. 


The last 15 years have witnessed a dramatic increase on the number of systemic therapies for the treatment of advanced HCC. Emerging data further showed that combined systemic therapy and LRT is associated with better efficacy than single-modality treatment. The promising response rates, longer time-to-progression, and potential in altering disease trajectory of the modern-era combination modality treatment have rendered it a promising downstaging therapy for LT. Yet, to date, few prospective data available. 


In this lecture, I would discuss the latest evidence on systemic therapy and combination therapy in management of patients with HCC and their potential application as down-staging treatment for liver transplantation.