The role of bridging locoregional therapy (LRT) for patients with hepatocellular carcinoma (HCC) within Milan criteria before liver transplantation (LT) has been controversial. Recently, Agopian et al. (1) retrospectively investigated the impact of bridging LRT on post-LT HCC recurrence and survival based on 3,601 patients undergoing LT from 2002 to 2013, collected in the US Multicenter HCC Transplant Consortium. They observed no significant differences in the recurrence-free survival (RFS) among patients not receiving RT and the type and combination of treatment modality [transarterial chemoembolization (TACE), thermal ablation (radiofrequency or microwave ablation), and others] used. The increasing number of LRT and the dynamic serum alpha-fetoprotein (AFP) changes were correlated with a higher risk of HCC recurrence. The authors concluded that LRT improved survival only in the subset of patients who achieved complete pathologic response (cPR) with a superior 5-year RFS of 72% compared to both untreated patients (69%; P=0.01) and LRT-treated patients not achieving cPR (67%; P=0.01). Admittedly, this is a benchmark study, and the authors should be congratulated on undertaking a sophisticated analysis in a large, heterogeneous cohort of patients.
However, several unanswered, critical questions are as follows: (I) since cPR is an unknown variable at the time of LT, who should receive bridging LRT? In this study, the selection criteria were highly variable and were affected by both patient (e.g., model for end-stage liver disease, AFP, and radiographical size and number of tumors) and center-specific factors (e.g., practice pattern and the anticipated wait-time according to the United Network for Organ Sharing region); (II) the data are lacking on whether patients had undergone any HCC treatments before listing, and the decision-making is again surgeon- or center-dependent, which might also have affected oncological outcomes (2,3); (III) the study comprises patients treated until 2013. Therefore, other modalities that recently emerged as an effective alternative LRT for HCC (e.g., drug-eluting beads TACE, Y90 radioembolization, and stereotactic radiation therapy) (4-6) should be considered when revising the liver allocation policy. In addition, dynamic AFP and other biological markers of aggressive tumor biology, such as neutrophil-lymphocyte ratio, C-reactive protein, and positivity for fluorine-18-fluorodeoxyglucose-positron emission tomography, should preferably be incorporated in patient selection (7); (IV) over 60% of patients in the study population had hepatitis C. Their viral status and whether they had received antiviral therapy post-LT, especially with the interferon-free regimens using direct-acting antivirals (8), have not being analyzed; (V) antineoplastic immunosuppression (9) and a novel immunotherapy using natural killer cells (10) might open up a new horizon to reduce post-LT HCC recurrence.
When we zoom out from the US, the problem gets even more complicated. A huge discrepancy exists in the treatment guidelines for HCC between East (11) and West (12). Of note, growing evidence suggests that laparoscopic liver resection might expand resectability in cirrhotic patients with HCC (13,14), making it difficult to standardize the indication of LT for HCC across the globe. Whether the acceptable range of HCC recurrence should be equivalent between living and deceased donor LT remains debatable.
The time has come for experts in the field of transplantation medicine and oncology to discuss in an international framework under the concept of “Transplant Oncology” (7) and provide a bona fide multidisciplinary cancer care for our patients in desperate need.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Agopian VG, Harlander-Locke MP, Ruiz RM, et al. Impact of Pretransplant Bridging Locoregional Therapy for Patients With Hepatocellular Carcinoma Within Milan Criteria Undergoing Liver Transplantation: Analysis of 3601 Patients From the US Multicenter HCC Transplant Consortium. Ann Surg 2017;266:525-35. [Crossref] [PubMed]
- Nathan H, Bridges JF, Schulick RD, et al. Understanding surgical decision making in early hepatocellular carcinoma. J Clin Oncol 2011;29:619-25. [Crossref] [PubMed]
- Nathan H, Segev DL, Bridges JF, et al. Influence of nonclinical factors on choice of therapy for early hepatocellular carcinoma. Ann Surg Oncol 2013;20:448-56. [Crossref] [PubMed]
- Song JE, Kim DY. Conventional vs drug-eluting beads transarterial chemoembolization for hepatocellular carcinoma. World J Hepatol 2017;9:808-14. [Crossref] [PubMed]
- Salem R, Gordon AC, Mouli S, et al. Y90 Radioembolization Significantly Prolongs Time to Progression Compared With Chemoembolization in Patients With Hepatocellular Carcinoma. Gastroenterology 2016;151:1155-63.e2. [Crossref] [PubMed]
- Meyer J, Singal AG. Stereotactic ablative radiotherapy for hepatocellular carcinoma: History, current Status, and opportunities. Liver Transpl 2018;24:420-7. [PubMed]
- Hibi T, Itano O, Shinoda M, et al. Liver transplantation for hepatobiliary malignancies: a new era of "Transplant Oncology" has begun. Surg Today 2017;47:403-15. [Crossref] [PubMed]
- Debes JD, de Knegt RJ, Boonstra A. The path to cancer and back: Immune modulation during hepatitis C virus infection, progression to fibrosis and cancer, and unexpected roles of new antivirals. Transplantation 2017;101:910-5. [Crossref] [PubMed]
- Geissler EK, Schnitzbauer AA, Zülke C, et al. Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial. Transplantation 2016;100:116-25. [Crossref] [PubMed]
- Ishiyama K, Ohdan H, Ohira M, et al. Difference in cytotoxicity against hepatocellular carcinoma between liver and periphery natural killer cells in humans. Hepatology 2006;43:362-72. [Crossref] [PubMed]
- Kokudo N, Hasegawa K, Akahane M, et al. Evidence-based clinical practice guidelines for hepatocellular carcinoma: The Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines). Hepatol Res 2015.45. [PubMed]
- Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698-711. [Crossref] [PubMed]
- Cheung TT, Dai WC, Tsang SH, et al. Pure laparoscopic hepatectomy versus open hepatectomy for hepatocellular carcinoma in 110 patients with liver cirrhosis: A propensity analysis at a single center. Ann Surg 2016;264:612-20. [Crossref] [PubMed]
- Hibi T, Kitagawa Y. Laparoscopic liver resection for hepatocellular carcinoma in cirrhotic patients: a potential game changer toward global standardization of care. Hepatobiliary Surg Nutr 2017;6:203-4. [Crossref] [PubMed]