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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 2  |  Page : 49-56

Transplantation in hepatocellular carcinoma - controversies and recommendations: A review of current literature


Department of Surgical Gastroenterology, HPB Surgery and Liver Transplantation, Sir Ganga Ram Hospital, New Delhi, India

Date of Submission30-Oct-2021
Date of Acceptance03-Dec-2021
Date of Web Publication30-Dec-2021

Correspondence Address:
Dr. Naimish N Mehta
R. No. 2222, Liver Unit, 2nd Floor, SSRB, Sir Ganga Ram Hospital, New Delhi - 110 070
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijamr.ijamr_220_21

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  Abstract 

Hepatocellular carcinoma (HCC) is the principal cause of death in patients with cirrhosis and the third leading cause of cancer-related death. HCC is present in around 80% of cirrhotic livers. Tumor recurrence and chronic liver failure are causative factors for mortality in the long term. Early liver transplantation (LT) for HCC with a significant tumor mass was associated with a poor prognosis owing to tumor recurrence. The vast experience and effectiveness of transplantation for HCC have sparked debates over whether the Milan criteria are overly stringent. The idea of tumor “downstaging,” expanding the limitations of tumor size, choice of either living related donor or cadaver donor transplantation, along with posttransplant care and its importance in HCC, are presently at the heart of a heated dispute. The recommendations in this article have attempted to highlight some of the disputed issues surrounding LT in HCC and may help programs in managing such patients better.

Keywords: Hepatocellular carcinoma, liver transplant, Milan criteria


How to cite this article:
Bhavsar R, Das SA, Mehta NN. Transplantation in hepatocellular carcinoma - controversies and recommendations: A review of current literature. Int J Adv Med Health Res 2021;8:49-56

How to cite this URL:
Bhavsar R, Das SA, Mehta NN. Transplantation in hepatocellular carcinoma - controversies and recommendations: A review of current literature. Int J Adv Med Health Res [serial online] 2021 [cited 2022 Aug 13];8:49-56. Available from: https://www.ijamhrjournal.org/text.asp?2021/8/2/49/334368


  Introduction Top


Hepatocellular carcinoma (HCC) is the principal cause of death in patients with cirrhosis and the third largest cause of cancer-related death.[1] The risk of perioperative mortality and morbidity related to portal hypertension and liver failure restricts resection in patients having severe liver dysfunction. HCC is present in about 80% of cirrhotic livers. The difficulties connected with the remnant cirrhotic liver and its continuing hepatocarcinogenesis are not addressed by surgical excision in HCC. Tumor recurrence and chronic liver failure are the leading causes of late mortality after resection. Recurrence rates have been reported to approach 60% in certain studies after 5 years, with just 10%–31% of recurrences being resectable. Previously early liver transplantation (LT) for HCC with a major tumor mass was associated with a poor prognosis owing to tumor recurrence.[2],[3],[4],[5] Only when the stricter Milan criteria were adopted (restricting the procedure to patients who had 1 lesion <5 cm, or 2–3 lesions <3 cm) was LT widely acknowledged as the most effective curative therapy for early-stage HCC.[6] Patients with HCC have a prognosis that is determined by the stage of the tumor at the time of diagnosis, with curative therapies accessible only for early-stage tumors. Transplantation of the liver can result in a 5-year survival rate of 70%.[7] However, the vast experience and effectiveness of transplantation for HCC has sparked arguments over whether the Milan criteria are overly stringent. The idea of tumor “downstaging” that expands the limitations of tumor size and/or number for either of living donor-related/dead donor-related LT (LDLT/DDLT), along with posttransplant care and its importance in HCC, are presently under dispute. This article examines the recent developments, debates, and recommendations on this contentious topic.


  Imaging in Diagnosis: Invasive versus Noninvasive? Top


Contrast-enhanced computed tomography (CT), rapid arterial enhancement (wash-in), and venous wash-out (portal venous) are diagnostic for HCC detection in cirrhotic livers. Two of every three lesions larger than one centimeter that do not show a characteristic wash-out may nevertheless be HCC, necessitating the use of another imaging modality for a definitive diagnosis. Without a confirmatory biopsy, currently existing imaging modalities cannot reliably diagnose hypovascular lesions.[8],[9] When compared to explant pathological testing, in more than a quarter of the cases during preoperative staging, the tumor burden was overstated, according to a retrospective review of UNOS data.[10] The current experience does not justify the use of 18F-fluorodeoxyglucose-positron emission tomography scanning. Some researchers have recently indicated that alpha-foetoprotein (AFP) values may have a role in the selection of HCC patients for LT.[11],[12],[13] An increased AFP is an indication of more advanced illness in the nontransplant situation. A rise in AFP concentration could indicate tumor aggressiveness, such as differentiation grade and vascular invasion, and hence a higher likelihood of recurrence. All of the above methodologies utilizing tumor biology indicators need to be validated further. Nonetheless, it is obvious that additional factors, in addition to tumor size and quantity, are significant and should be considered when selecting HCC patients for LT.

Recommendations

  1. CT and magnetic resonance imaging (MRI) help to stage patients prior to surgery
  2. The BCLC staging method is the best for predicting the prognosis of HCC patients
  3. The Tumour Nodes Metastases (TNM) system (8th Edition), which combines pathological evaluation of the liver and assessment of microvascular invasion, should be used to determine prognosis after transplantation
  4. High-resolution CT of the chest, as well as that of the abdomen and pelvis, should be used for extrahepatic staging
  5. Tumor biopsy should be avoided in cirrhotic patients undergoing LT who have evidence of HCC on diagnostic modalities and a lesion >1 cm
  6. Noninvasive imaging does not allow for a reliable diagnosis in individuals with lesions smaller than or equal to 10 mm, and it should not be used to make a decision for transplantation.



  Listing of Patients for Transplantation: Beyond Milan Criteria? Top


A “managed” or moderate increase in tumor size above the Milan criterion can result in posttransplant survival comparable to patients who meet the criteria.[14],[15] The most important factor is the definitions used in selection to identify people who, despite exceeding the Milan criteria, can still perform well without increasing recurrence.[16] [Table 1] lists the Milan criteria and various other criteria expanded to include more patients for transplantation.
Table 1: Milan criteria and various criteria beyond it - “Expanded criteria”

Click here to view



  The Milan Criteria and Beyond: The “Metro Ticket” Top


A 5-year survival rates of 70% or higher after LT, if within Milan Criteria, has been reported in many studies, whereas other authors have concluded that extension of tumor size outside the Milan criteria can attain posttransplant survival rates comparable to those within the Milan criteria. Several studies have proposed expanding DDLT for patients outside the Milan criteria [Table 1]. This concept has been compared to the European Metro system, with the example of “the greater the distance, the higher the price” [Figure 1]. The Milan criteria's best reported results of 75%–80% 5-year expected survival rates are comparable to other studies having reported a similar 5-year survival rate of 50%–70% using the Milan criteria which is comparable to LT done for those outside the Milan criteria [Figure 1].[24],[25]
Figure 1: Beyond the “Metro Ticket” concept and its outcomes

Click here to view



  Criteria for Choosing Patients: Extended Criteria - What Should the Limits Be? Top


The criteria and features, except the size and number of tumors such as poor differentiation with microvascular invasion, are related to poor outcomes in a study by Cilo et al., who reported a lower dropout and 3-year intention-to-treat survival (69% within Milan criteria and 85% exceeding Milan criteria), with no recurrence seen.[5],[26] Using a modified TNM staging classification, Marsh et al. also reported a positive outcome.[27]


  METROTICKET 2.0 Model: Predicting Risk of Death after Transplantation Top


This model [Figure 2] predicts posttransplantation prognosis and outcomes on basis of the inclusion of AFP. This simplified AFP adjusted-to-HCC size criteria increased to 3 (the cut-offs suggesting restrictions for HCCs considered for transplantation, i.e., 200 ng/mL for the up-to-7 tumors [number of tumors summed to the size of tumor nodules]; 400 ng/mL for the up-to-5; and 1000 ng/mL for the up-to-4) in comparison to other AFP-based criteria. Such AFP cut-offs showed a reduction in survival when pretransplantation AFP levels rise. This model calculates outcomes based on the pretransplantation AFP level that allows tumor reassessment during the waiting period, while the response to neoadjuvant treatment can be considered a marker of tumor aggressiveness. AFP threshold level for predicting prognostic significance has not been shown and the model's inverse association between AFP and tumor architecture may refine priority among HCC patients and identify waiting list dropouts.[28]
Figure 2: METROTICKET 2.0 Model. Variations in the number of nodules, diameter of the biggest nodule, and alpha-foetoprotein predict hepatocellular carcinoma-specific survival after 5 years following liver transplantation[28]

Click here to view


Recommendations

  1. Consider LT if 5-year survival rate is the same as non HCC patients
  2. The size/overall diameter of tumors should be considered a major factor, with Milan criteria considered the gold standard to assess other criteria
  3. Expanded criteria to be used to explore survival in patients beyond Milan criteria
  4. AFP concentrations alone can be utilized with imaging criteria to make transplantation decisions
  5. Microvascular invasion should not be used as an indication for LT in HCC since it cannot be reliably detected before transplantation.



  The Cirrhotic versus the Noncirrhotic Liver - Role of Transplantation Top


HCC in the noncirrhotic liver is rare (10%–15%) with an average disease-free survival of 5-year and an overall survival of 49%.[29],[30],[31],[32] A noncirrhotic HCC with 2 nodules, no nodal/macrovascular invasion, and R0 resection is an unlikely occurrence. The diagnosis is frequently made at a late stage in such people. When possible, resection is the recommended treatment option since people with healthy livers tolerate major resections well. However, the probability of local recurrence (30%–73%), 5-year survival (25%–81%), and disease-free survival (DFS) (24%–54%) has been seen in various studies on patients with cirrhosis.[33],[34] Macrovascular and lymph-node invasion, as well as early recurrence (less than a year) following resection, were all significant risk factors for a poor prognosis. The initial HCC's tumor diameter and Milan criteria had no bearing on the outcome. Only a few examples of primary LT in noncirrhotic individuals with HCC have been reported.[32],[35]

Recommendations

  1. HCC in noncirrhotic livers is not eligible for the Milan criterion or its modifications
  2. Nonresectable HCC in noncirrhotic patients without any macrovascular invasion or extrahepatic dissemination are suitable for transplantation
  3. Salvage transplantation to be considered in noncirrhotic patients undergoing resection with intrahepatic recurrence with no macrovascular invasion or extrahepatic spread.



  Salvage Transplantation Postresection: Feasibility Top


The salvage liver transplant (SLT) used to treat individuals who had recurrent HCC or had liver function deterioration after undergoing primary hepatic resection was first proposed by Majno et al. to deal with the growing waiting lists for liver transplants.[36] Due to a history of prior resection, significant adhesions, aberrant anatomical features, and more enhances the complexity and danger of surgery. The mortality rate with SLT was studied to be as high as 28.6% in the early stages, which was much greater than that of primary LT (PLT) (2.1%).[37],[38] PLT is regarded to be an appropriate alternative for the treatment of HCC with hepatic cirrhosis since it has lower blood loss and hazards than SLT. Multiple surgical procedures, as well as adjuvant treatments like radiation, will make the surgery more challenging during SLT. It is recommended to dissect the porta-hepatis first, clamp the inferior vena cava, then mobilize and swiftly remove the diseased liver to minimize bleeding and the danger of tumor metastasis during the procedure to face the challenges presented as a result of previous surgery and adhesions.[39]

Recommendations

  1. SLT following hepatic resection can reach the same good clinical effectiveness with proper preoperative assessment and an accurate surgical operation.



  Management of Hepatocellular Carcinoma for Patients on the Waiting List Top


Death, tumor growth, or spread that exceeds permissible limits, and deterioration in clinical state that precludes transplant result in drop-out rates from the waiting list. The rate of dropout is directly proportional to the time for organ allocation with higher rates matching with longer waiting; this period is very variable and is influenced by factors such as the patient's blood group and geographic location. The main concern whilst on the waiting list is how to limit the danger of tumor progression beyond the selection criteria and then de-listing.

The controversial strategies that have been suggested and discussed to overcome this problem are.

Allocation of Model for End-Stage Liver Disease points for hepatocellular carcinoma: Reduced waiting times or higher mortality?

The Model for End-Stage Liver Disease (MELD) score calculated using serum creatinine, bilirubin, and INR, offers an objective value that accurately predicts short-term mortality and helps in improving waiting list mortality and access to transplant.[40],[41],[42] To reduce waitlist dropout by the progression of their liver illness an original HCC MELD score was created, which reflected the risk of dropout, compared to mortality.[43] T1 lesions (single tumor <2 cm) was given a 24 point MELD score, whereas T2 lesions (beyond T1 but within the Milan criteria) were given 29 points. In comparison to the pre-MELD era, transplant for HCC increased from 7% to 22% with commensurate improvements in the number of transplants performed, the length of time on the waiting list, and the number of people who drop out while on waiting list.[44] Furthermore, HCC patients had a better prognosis over non HCC patients with similar MELD scores.[45] Additional factors of tumor biology (changes in serum AFP, sensitivity to ablative therapy, and volume doubling time) are incorporated into such models to develop HCC priority reflecting the dropout risk while reduction in recurrence risk.

Recommendations

  1. Radiological Imaging and AFP level should be used to monitor the waiting list on a regular basis.



  Model for End-Stage Liver Disease Exception Points for Hepatocellular Carcinoma: Higher Transplant Rates Top


LT is an effective curative therapy for HCC. For the allocation MELD, exception points are allocated to HCC patients to represent priority on waiting list and related mortality. A 6-month observation period and a maximum score of 34 points are required under the most recent adjustment in allocation rules. Although MELD ratings predict 3-month death in most cirrhotic patients, they underestimate the risk of mortality and waiting list dropout in HCC patients. In a research by Heimbach and colleagues, it was observed that HCC patients with an early MELD exception score of 22 and a 3-, 6-, or 9-month wait before receiving 25, 28, or 29 exception points received greater transplant rates than non HCC candidates. The researchers concluded that delaying LT for 6–9 months minimizes the discrepancy in transplant rates.[46],[47]

Recommendations

  1. Patients with a MELD exception score of 22 to be given priority listing
  2. Increasing score every 3 months
  3. After a 6-month waiting period, listing with a MELD exception score of 28 points, which increases every 3 months to a maximum score of 34 points.



  Downstaging before Transplantation Top


Locoregional therapy reduces tumor size and number (no downstaging contraindications) in patients who initially do not meet locally acceptable criteria for transplant.[41] The survival in patients treated by downstaging was similar to transplant waitlisted candidates.[48],[49] Vascular invasion and extrahepatic disease are considered unequivocal contraindications for downstaging.


  Bridge Therapy/Downstaging before Liver Transplantation: Resection versus Ablative Therapies Top


In patients who have previously been enrolled for LT, resection can be utilized as a “bridge” therapy. The cornerstones of “bridge” therapy have been transarterial chemoembolization (TACE) and percutaneous ablation, such as radiofrequency ablation; these therapies may only accomplish partial tumor and nodule necrosis and can lead to increase tumor recurrence following LT.[50],[51] However, these are linked to an elevated risk as subsequent LT may also become difficult and is only recommended for patients with Child A or B cirrhosis. The adoption of minimally invasive techniques like laparoscopic/transthoracic methods for peripheral tumors may help to inflate this strategy.[50],[52],[53],[54]

Recommendations

  1. 5-year survival rate equivalent to HCC patients is a must for the patients undergoing downstaging before transplant.
  2. Tumor size and the number of viable tumors, and AFP monitoring should be considered during downstaging.



  Living Donor Related Liver Transplantation Versus Dead Donor Related Liver Transplantation: Donor Safety versus Retransplantation Top


In certain places, particularly in Asia, where deceased-donor organs are few or unavailable, LDLT utilizing a healthy donor's right or left hemiliver is the sole option for LT. The most serious worry with LDLT is donor safety, as there is a small risk of complications or death.[55] Six studies compared DDLT versus LDLT for HCC.[56],[57],[58],[59],[60] When graft failure develops following LDLT, deceased-donor organs are commonly used.[61] Even if more stringent criteria were used, the expert panel supported the use of deceased-donor grafts for failed LDLT. Retransplantation because of graft failure following LDLT is unusual, but when it occurs, outcomes are typically favorable. Thus, patients who received a living-donor-related graft and satisfied the standard liver transplant criteria should be considered for retransplantation.

Recommendation

  1. For HCC patients with a 5-year survival comparable to that of corresponding staged patients undergoing DDLT, LDLT is appropriate, considering the psychosocial factors for both donor and recipient
  2. To reduce donor risk and improve recipient outcomes, LDLT should be limited to centers of expertise in liver surgery and transplantation, with retransplantation for graft failure considered
  3. Retransplantation with a dead donor organ for graft failure is not recommended in patients who have had LDLT for HCC outside of the defined geographical criteria for DDLT.



  Immunosuppression Postliver Transplantation: Immunosuppression or Anticancer Therapy Top


Immunosuppressive drugs, aside from mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus), enhance the proliferation of malignant cells, including HCC cells, according to research. In malignant cells, cyclosporin A enhances invasiveness and impairs DNA repair, whereas tacrolimus promotes proliferation in animal models.[62],[63],[64] Tumor doubling time is dramatically reduced when they are exposed to these calcineurin inhibitors.[65] Because mTOR is expressed in over 60% of HCCs, using mTOR inhibitors is indicated in the majority of cases.[66],[67],[68] The only treatment linked with better posttransplantation survival unique to HCC patients (and not non HCC patients) was sirolimus-based immunosuppression, adding to the clinical evidence of its anticancer characteristics. Anti-CD25 antibodies were found to have similar effects on survival in both HCC and non-HCC patients. These findings, together with prior studies that combined anti-CD25 antibody induction with delayed CNI introduction, support the use of these drugs following LT.[68] There are no studies suggesting that reducing immunosuppression after LT reduces recurrence.

Recommendation

  1. Outside of clinical studies, no recommendation for the use of mTOR inhibitors alone to reduce the risk of HCC recurrence can be made based on existing findings.



  Recurrences Following Liver Transplantation: Role of Sorafenib versus Locoregional Therapy Top


The most serious concern is the likelihood of tumor recurrence after LT for HCC, which occurs in 8%–20% of patients in the first 2 years, with a median survival time of <1 year from the time of diagnosis.[69] Regular imaging and AFP monitoring enabled for the early diagnosis of a recurrence.[70] Sorafenib, a multitargeted tyrosine kinase inhibitor, has anticancer benefits in advanced HCC and is now being investigated as adjuvant therapy (STORM trial). Licartin, a 131I-radiolabeled murine monoclonal antibody that selectively targets HCC, affects tumor recurrence prevention and survival in a randomized double-blind trial.[71],[72] De novo HCC must be differentiated from recurrent hepatitis C and advancing fibrosis HCC, which develops later and is most commonly associated with recurrent hepatitis C and advancing fibrosis. When technically viable, locoregional recurrence therapy, such as liver resection, radiofrequency ablation, or TACE, has been utilized successfully in individuals with minimal disease. Sorafenib has been used with care in the past.[73]

Recommendation

  1. 6–12 monthly contrast-enhanced CT or MRI imaging, as well as AFP tests, may be part of the posttransplant monitoring protocol
  2. HCC recurrence after transplant is treated with surgery for resectable lesions or locoregional or systemic treatment (including sorafenib) for unresectable lesions
  3. In the case of recurrent HCC, liver retransplantation is not an option.



  Outcomes Related to Transplantation in Hepatocellular Carcinoma Top


Significant controversy exists regarding the choice between transplantation and resection/locoregional therapies in the management of patients with well-compensated cirrhosis (i.e., patients with Child-Pugh class A disease and selected patients with class B disease) and early HCC. HCC recurrence after transplant has recently been added to the list of tumors that can be treated with surgery for resectable lesions or locoregional or systemic therapy (including sorafenib) for unresectable lesions. In one trial, transplantation was shown to be superior than resection, whereas, in the other, resection was found to be superior. In various meta-analyses, it has been shown that patients with early HCC have a significant 5-year survival advantage after undergoing transplantation compared to resection and in patients with well-compensated cirrhosis a statistically significant improvement in 5-year OS undergoing transplantation versus resection.[73] When comparing SLT versus PLT, SLT is a clinically favorable treatment option for both surgeon and patient in general. The survival after SLT is relatively lower than PLT for 1-, 3-, and 5-year overall survival. In clinical practice, the controversy surrounds the recurrence rate following SLT versus PLT. There was no significant difference seen between the 1-year and 3-year disease-free survival rates for PLT versus SLT, but 5-year disease-free survival rate is higher among SLT recipients with a higher rate of tumor recurrence due to longer time interval from the diagnosis to LT.[74]


  Conclusion Top


LT is an important part of the treatment of HCC patients since it offers the best chance of long-term recurrence-free survival. Despite the fact that the Milan criteria are the most widely accepted transplant criteria in the United States, some people believe they are overly rigorous and have caused continued disagreement about the best patients to choose. Although LT may assist some patients with smaller (UNOS T1) or bigger (expanded criteria with or without downstaging) lesions, the advantages must be balanced against the risks to others on the waiting list due to restricted organ availability. The recommendations highlighted in this article address the most contentious issues regarding HCC LT and may help transplantation programs around the world better manage their HCC patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Imaging in Diagn...
Listing of Patie...
The Milan Criter...
Criteria for Cho...
METROTICKET 2.0 ...
The Cirrhotic ve...
Salvage Transpla...
Management of He...
Model for End-St...
Downstaging befo...
Bridge Therapy/D...
Living Donor Rel...
Immunosuppressio...
Recurrences Foll...
Outcomes Related...
Conclusion
References
Article Figures
Article Tables

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