Transplantation Oncology: Liver Transplantation to treat Liver Cancer

Transplantation Oncology: Liver Transplantation to treat Liver Cancer.  Although multidisciplinary integration has promoted the continuous development of transplantation oncology, there are still many difficulties in the treatment of liver cancer with liver transplantation. The prevention and treatment of tumor recurrence and the exploration of further mechanisms are still the direction of long-term efforts in the future.

1.  Traceability

With the increasing advancement of surgical techniques and the maturity of perioperative management, organ transplantation is developing rapidly, and it has become an effective method for the treatment of end-stage organ diseases and organ failure. In many large-scale transplant centers around the world, organ transplantation has become a routine surgical treatment method.

The continuous strengthening of the concept of multidisciplinary comprehensive treatment has made the connection between transplantation and oncology increasingly closer. In this context, a new sub-discipline-transplantation oncology has emerged.

At the beginning of the 21st century, the American magazine Dermatologic Surgery launched a special issue of “Challenges and Opportunities in Transplant Oncology”, focusing on the prevention and treatment of new skin tumors after transplantation. In 2014, the concept of “liver transplantation oncology” was first proposed by Professor Yaszo Hibita, a liver transplant expert at Kumamoto University in Japan. At present, transplantation oncology has far exceeded the scope of pure surgery.

It is the intersection, integration, penetration and promotion of surgery, oncology, immunology, organ preservation, immunosuppressive pharmacology, imaging and other related disciplines. The comprehensive discipline formed, which focuses on all transplant recipients under immunosuppression, and takes all oncology issues in transplantation medicine as the subject boundary. As an emerging discipline, transplantation oncology has opened up a new era of liver transplantation for the treatment of malignant tumors, and will help clinicians to better achieve precise treatment of liver cancer.

2.   Multidisciplinary integration promotes liver transplantation oncology

The development of liver transplantation oncology brings together multidisciplinary forces, including clinical disciplines such as hepatobiliary and pancreatic surgery, internal medicine oncology, gastroenterology and anesthesiology, as well as clinical auxiliary disciplines such as radiation oncology, pathology and immunology.

Many years ago, the exploratory practice of liver transplantation gave birth to the emergence of liver transplantation oncology. In recent years, the multidisciplinary integration of liver transplantation is a vivid portrayal of the development of transplantation oncology. Through in-depth understanding of the treatment of liver cancer in the era of transplantation oncology, we can get a glimpse of the development trend of the entire field of transplantation oncology.

Hepatocellular carcinoma is the second cause of cancer death in some countries [1]. In recent years, liver transplantation has gradually become one of the main treatment methods for liver cancer. The annual number of liver transplants for liver cancer in some countries accounts for 30% to 40% of the total number of liver transplants.

The shortage of donor livers and postoperative tumor recurrence are currently the core bottlenecks restricting the development of liver cancer liver transplantation, and are also the main problems that need to be solved urgently in the transplantation community.

3.  Liver Transplant Oncology-A New Exploration of Accurate Diagnosis and Treatment of Liver Cancer

3.1 Realize reasonable and accurate selection of liver cancer liver transplant recipients

How to select recipients reasonably is the core issue of liver transplantation for liver cancer. More and more evidence [2-3] indicates that tumor morphology is only one of many factors that affect the prognosis of liver cancer liver transplantation.

Therefore, various transplant centers continue to explore and expand the selection criteria for liver cancer liver transplant recipients, and gradually break through the tumor morphology Academic restraint [4-9], the classic standard represented by the Milan standard and the new standard modeled by the Hangzhou standard, have greatly improved the prognosis of liver transplant recipients with liver cancer [10].

The changes in liver transplantation standards for liver cancer, from the initial morphological standards based on the size and number of tumors, to the introduction of tumor pathological features and molecular markers to expand the selection criteria, are precisely surgery, imaging, pathology, and molecular biology. A vivid manifestation of the continuous cross and integration of multiple disciplines.

As one of the promising non-invasive detection methods in the era of precision medicine, the role of liquid biopsy in the field of organ transplantation is gradually being discovered. Liquid biopsy is that almost all molecules in human body fluids can be “captured” by it and perform multi-omics detection and bioinformatics analysis, and then used to guide clinical diagnosis and treatment.

Combined use of liquid biopsy and deep learning and other technical means to use preoperative serum tumor markers, inflammatory factors and metabolic molecules in liver cancer liver transplant recipients to establish molecular classification of liver cancer, and compare the existing liver cancer liver transplantation standards The combination can significantly improve the predictive performance of postoperative tumor recurrence and optimize recipient selection [11].

3.2 Expanding the beneficiaries of liver cancer patients

Due to the shortage of donor livers and other reasons, it is an international consensus to choose liver cancer patients with low risk of recurrence to receive liver transplantation. In recent years, the rapid development of tumor treatment methods represented by intervention, radiotherapy (radiotherapy), chemotherapy (chemotherapy), etc., has enabled some liver cancer patients who exceed the indication standards to be re-incorporated through down-stage treatment to reduce liver cancer stages. Waiting list for liver transplantation. Downstage treatment methods mainly include hepatic artery chemoembolization (TACE), radiofrequency ablation (RFA), etc. [12].

Patients who meet the indications for liver transplantation for liver cancer are also at risk of tumor progression while waiting for liver transplantation, while bridging or over-treatment is to control tumor progression through TACE or RFA while waiting for liver transplantation. Complete pathological remission (CPR) of tumors caused by interventional bridging therapy is considered to be an effective predictor of tumor recurrence and patient prognosis after liver transplantation [13].

However, repeated local treatments also have many disadvantages, such as liver damage, changes in tumor biological behavior, and hepatic artery damage. Therefore, optimizing the treatment plan and achieving CPR as much as possible is one of the goals of liver cancer bridging treatment before liver transplantation. Immunotherapy represented by immune checkpoint blocker (ICI) is a breakthrough in the treatment of advanced liver cancer in recent years. However, ICI applied to organ transplant recipients has the risk of inducing fatal acute rejection [14].

Vanderbilt University in the United States reported the first case of liver cancer before liver transplantation using programmed death receptor 1 (PD-1) monoclonal antibody to cause fatal immune injury after transplantation [15]. Therefore, patients with liver cancer who are planning to undergo liver transplantation should be cautious when receiving PD-1 monoclonal antibody treatment. At present, domestic scholars are carrying out clinical trials related to immunotherapy during perioperative period of liver transplantation for liver cancer.

3.3 Promote changes in concepts and methods of surgical treatment of liver cancer

The techniques of liver surgery, surgical instruments, ultrasound, and imaging continue to advance. At the same time, it has also brought about continuous changes and updates in liver cancer surgery preoperative evaluation, treatment concepts, and technical details. Relying on the increasingly perfect preoperative evaluation system, liver surgeons can clearly locate tumors and clarify the adjacent relationship between tumors, making it possible to implement resection of tumor-bearing liver segments and reflux areas.

The surgical area goes deep into the hilar and caudate lobe of the previous “surgical restricted areas”. The precision liver resection, which is characterized by segmental and sub-segment resection, has gradually become popular, achieving the goal of anatomical liver resection as well as Preserving more liver parenchyma effectively improves the treatment effect and the resectable rate of liver cancer [16]. The proposal and implementation of a series of concepts such as “save liver cancer liver transplantation” and “sequential liver cancer liver transplantation” have not only alleviated the pressure of clinical donor liver shortage, but also reflected that the surgical treatment of liver cancer has become more flexible.

The radical treatment of recurring tumors after surgery has moved from “passive liver transplantation” to “active liver transplantation”. The “autologous liver transplantation” that has emerged from the application of complicated liver resection techniques, organ hypothermic perfusion preservation techniques, venous bypass techniques, and liver transplantation tube anastomosis to liver transplantation not only reduces the risk of partial complex liver resections, but also makes Patients with liver cancer who cannot be operated on in vivo have regained the opportunity for surgery.

3.4 Monitoring of tumor recurrence and metastasis after transplantation is becoming more and more accurate

The recurrence of liver cancer after liver transplantation is still a serious challenge to be faced. Although the recipient is accurately selected according to liver transplantation standards, the 5-year recurrence rate of liver cancer after liver transplantation is still as high as 30% [17]. How to establish an effective tumor recurrence and metastasis monitoring system with a view to “early detection” and “early intervention” is a research hotspot in the field of transplantation. Regular follow-up after operation, related molecular biological indicators combined with imaging examination, will help early detection of tumor recurrence and metastasis. In view of the complex biological characteristics of liver cancer, in addition to AFP, a classic indicator for predicting postoperative tumor recurrence, more sensitive molecular biological indicators and more effective methods are needed to detect postoperative recurrence in recipients.

The rapid development of precision medicine and high-throughput bioinformatics technology has promoted the continuous advancement of research in this field. In recent years, vitamin K deficiency-induced proprotein or antagonist II (PIVKA-II), inflammation-related biological markers, and AFP have emerged. Plastids and circulating tumor cells, etc. In addition, considering that the transplant recipient is in an immunosuppressive environment for a long time after surgery, the immune function of the body is monitored after the operation, and the intensity of immunosuppression is adjusted in time to reduce the recurrence of liver cancer after liver transplantation. At present, the indicators commonly used to monitor the immune function of patients include Lymphocyte subsets (B lymphocytes, T lymphocytes and natural killer cell levels, CD4/CD8 ratio), CD4+ T lymphocyte activity, cytotoxic T lymphocyte activity, IL-2 and other cytokine levels, and neutrophils / Lymphocyte ratio, etc. [18-19].

3.5 Expand the source of donor liver and alleviate the shortage of donor liver

In order to solve the problem of the shortage of donor livers, in addition to carrying out living donor liver transplantation and split liver transplantation, increasing the utilization rate of expanded standard donor livers is an important way to expand the source of donor livers. The expanded standards of donors mainly include: age> 60 years; bullous steatosis of the donor liver> 30%; donor stays in the intensive care unit> 7 days. Risk factors for hemodynamics include: long-term hypotension, dopamine for more than 6 hours to maintain blood pressure; or the need for two vasoconstrictor drugs to maintain blood pressure for more than 6 hours; cold ischemia time> 12 hours; before aortic blockage Hypernatremia.

In addition, donors such as ABO blood group incompatibility and positive serum virology, suffering from extrahepatic malignant diseases, active bacterial infections and high-risk lifestyles also fall into this category. The author’s research team [20] established a new plan for the precise treatment of liver cancer with ABO blood type incompatible liver transplantation, so that more patients with liver cancer that meet the Hangzhou standard can benefit significantly from ABO blood type incompatible liver transplantation, and the number of beneficiaries is nearly 3% higher than the national average. It is safe and effective to expand the source of donor liver, effectively alleviating the shortage of donor liver. Expanding the standard donor liver expands the source of donor livers, but also increases the incidence of postoperative complications such as non-functioning primary grafts and delayed recovery of graft functions.

As a new generation of organ preservation technology, mechanical perfusion overcomes many shortcomings of traditional static cold preservation technology. Among them, the normal temperature mechanical perfusion technology has shown extraordinary advantages in repairing and expanding the standard donor liver, evaluating the quality of the donor liver, and in vitro intervention treatment, providing technical support for the transformation of transplantation from “passive” to “active”. The root of the shortage of organ sources is the insufficient number of donors, which is determined by the current donor-recipient separation organ transplantation model. What follows is a series of problems such as immune rejection of allogeneic transplantation, which is one of the limitations of the current organ transplantation model.

The arrival of room temperature mechanical perfusion technology will trigger new changes in the model of organ transplantation, that is, combined with artificial liver support systems and new treatment methods, making it possible to repair the recipient’s organs in vitro and autologous transplantation. The continuous improvement and innovation of donor organ preservation methods are the result of the integration of multiple disciplines such as surgery, basic medicine, pharmacy, biomedical engineering and even materials science. It is these different disciplines and theories that intersect each other and the gradual maturity of donor organ preservation technology has given birth to breakthroughs in donor organ preservation theory and technology in the field of liver transplantation.

3.6 Liver transplantation for different types of liver tumors

Transplantation oncology involves various diseases. Various types of transplantation techniques and various types of organ transplantation are exploring the treatment of refractory tumor diseases of various organs. In terms of disease types, it includes liver benign and malignant tumors, colorectal cancer liver metastases, neuroendocrine tumors liver metastases, and so on. Judging from the age of patients, with the maturity of adult liver transplantation technology, pediatric liver transplantation is gradually emerging in major liver transplantation centers in China. After continuous exploration and research, the current 1-year survival rate after liver transplantation is nearly 90%, and the 3-year survival rate is nearly 80%. The survival rate of children after liver transplantation is better than that of adults.

The liver is the most common metastatic organ for colorectal cancer. For a long time, local resection is the only treatment method for liver metastasis of colorectal cancer, but only 30% to 40% of patients meet the resection criteria when the disease appears [21]. The main reason why patients with liver metastases from colorectal cancer cannot undergo partial hepatectomy is insufficient residual liver capacity. Therefore, for patients with insufficient residual liver and no extrahepatic involvement, liver transplantation is becoming an option [22].

A study from the University of Oslo, Norway [23] showed that the 5-year expected survival rate of liver transplantation for patients with liver metastases from unresectable colorectal cancer reached 60%. Currently, a number of relevant clinical studies are underway. The establishment of objective and accurate selection criteria and evaluation systems and standardized chemotherapy regimens will help improve the efficacy of liver transplantation with liver metastases from unresectable colorectal cancer. Neuroendocrine tumors are a type of heterogeneous tumors that originate from peptidergic neurons and neuroendocrine cells and can produce biologically active amines and/or peptide hormones.

Liver metastases are common in neuroendocrine tumors originating from the small intestine and pancreas [24]. Surgical resection is the best treatment for liver metastases of neuroendocrine tumors, but liver metastases often involve multiple liver lobes and occur frequently. Therefore, liver transplantation has become a potential candidate treatment method [25]. Mazzaferro et al. [26] formulated the indication standards for liver transplantation in patients with neuroendocrine tumor liver metastases: (1) G1/G2 classification of the World Health Organization tumor classification standard; (2) The primary tumor is drained by the portal vein system; (3) ) Liver involvement <50%; (4) Complete removal of the primary tumor; (5) Stable disease or effective treatment for extrahepatic diseases for at least 6 months; (6) Age <60 years (relative standard). The 5-year and 10-year survival rates of patients meeting the above criteria were 97% and 89%, respectively. Hepatoblastoma is the most common liver tumor in children, and its incidence has continued to rise in the past 20 years. Comprehensive treatment of hepatoblastoma is effective.

Surgical resection combined with chemotherapy is the main treatment method [27-29], and the 5-year cumulative survival rate is as high as 80%. After chemotherapy, it is evaluated as POST-TEXT stage IV or POST-TEXT stage III with hepatic vein or inferior vena cava and other important blood vessels involved, and liver transplantation can be considered in cases where surgery cannot be performed [30]. In short, surgical resection is the main treatment for low-risk tumors; patients with high-risk tumors or patients who require complicated liver surgery or transplantation should be referred to a specialist center as soon as possible.

4. The future of transplantation oncology

Although multidisciplinary integration has promoted the continuous development of transplantation oncology, there are still many difficulties in the treatment of liver cancer with liver transplantation. The prevention and treatment of tumor recurrence and the exploration of further mechanisms are still the direction of long-term efforts in the future. As a complex systemic disease, malignant tumors can be abnormal and closely related at the level of genome, transcriptome, proteome, and metabolome. Single-omics studies are not enough to clarify the complex pathogenesis of tumors.

In the era of big data, multi-omics research on tumors is in the ascendant, and new multi-omics technologies will surely play an important role in the development of transplantation oncology. The deep integration of multi-omics and organ transplantation, multi-omics integrated analysis and artificial intelligence research are expected to more accurately reveal the molecular characteristics of tumors, overcome tumor heterogeneity, and provide an important basis for the precise and individualized treatment of tumors.

An important scientific method for donor-recipient screening, diagnosis, prognostic evaluation, and efficacy evaluation. In addition, the rapid progress of immunotherapy will also benefit organ transplantation at the intersection of tumor immunity and transplantation immunity, and ultimately improve the overall efficacy of liver transplantation for liver cancer and benefit more patients.

(source:internet, reference only)

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