Hepatocellular Carcinoma: The Search for Innovative Adjuvant Therapies

This review summarizes the current data on efficacy and rationale of adjuvant treatment for hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT). The authors review prognostic factors for disease recurrence and adjuvant therapy after OLT, including systemic chemotherapy, intra-arterial chemoembolization, immunosuppressant effects, and sorafenib (Nexavar). Several interesting questions are raised in the article, including: (1) When is the best time to apply systemic chemotherapy? (2) Is there overlapping toxicity of chemotherapy and immunosuppressant agents, which could potentially lower survival rate? (3) Should patients with higher risks of recurrence (beyond Milan or University of California, San Francisco [UCSF] criteria) be selected for clinical trials in order to increase the sensitivity of those investigations? (4) Is development of a scoring system that can be applied to adjuvant studies after OLT important for predicting recurrence? (5) Should novel agents like sorafenib or new molecular markers be studied in adjuvant trials in patients with higher risks? HCC is one of the most common malignancies worldwide, with more than half a million new cases reported annually. Conventional chemotherapy, radiotherapy, hormone blockade, and several innovative agents have failed to achieve a significant survival benefit in patients with the disease.[1] Surgical resection, ablation, and liver transplantation have been considered as potential curative methods for HCC. However, only about 30% to 40% of HCC patients are amenable to such curative treatments because HCC diagnoses have almost always occurred at later stages.[2]

Recurrence Issues
Because of the scarcity of donor livers, there is little evidence within the organ allocation system for posttransplantation HCC recurrence. High recurrence rates and poor outcomes are shown when HCC recipients have advanced disease characterized by macroscopic vascular invasion, lymph node involvement, and extrahepatic spread.[3] Although the decision to expand patient selection beyond the Milan criteria is still controversial, tumor recurrence is the inevitable question we are facing.

Although the precise mechanism of recurrence is vague, preoperative or intraoperative microscopic metastases are likely responsible for recurrent disease, as well as possible immunosuppressive status post-OLT.[4,5] Hepatocellular carcinomas are inherently chemotherapy-resistant tumors and are known to overexpress the multidrug resistance genes.[6,7] Survival is not guaranteed in either palliative therapy for patients with recurrent HCC after OLT or in the treatment of primary HCC using chemoembolization.[8] Therefore, the development of innovative, alternative adjuvant therapies for recurrent HCC should be our goal.

Recent Investigations
Sorafenib was recently discovered to be a multitargeted small-molecule tyrosine kinase inhibitor that impedes tumor growth and angiogenesis.[9] In the recent Sorafenib HCC Assessment Randomized Protocol (SHARP) trial, median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55–0.87; P < .001). We agree with Kim and coauthors that this novel agent should be studied post-OLT in an adjuvant setting.

Adjuvant immunotherapy of cancer is attractive because of its high specificity, low systemic toxicity, and decreased drug interactions. HCC is a potential target for this type of treatment as these tumors are often infiltrated with lymphocytes, and patients with high levels of tumor-infiltrating lymphocytes were found to have a better prognosis after resection.[10] Cases of spontaneous regression also suggest that immune mechanisms are important in the control of HCC.[11,12] Current immunotherapy trials targeting HCC include several strategies-adoptive transplantation of cytokine-activated killer cells and cytotoxic lymphocytes, cell-based vaccine by infusion of antigen-presenting cells like the dendritic cell (DC), tumor antigen-based vaccines using autologous tumor plus cytokines, tumor-specific antigen like alpha-fetoprotein (AFP)-derived peptide, AFP-coding DNA, or recombinant viral vectors coding for AFP genes.[13-16]

In the largest trial of adoptive therapy for HCC, 150 patients were randomized to receive either interleukin (IL)-2 (Proleukin) and anti-CD3–activated peripheral blood lymphocytes or observation alone after curative resection. The results showed a lower recurrence rate, longer time to recurrence, and longer recurrence-free survival in the immunotherapy group-all statistically significant-but the difference in overall survival fell short of statistical significance at P = .09.[17]

In another trial, 20 advanced HCC patients received dendritic cells (DCs) pulsed with autologous tumor lysate. These patients had a significantly improved 1-year survival rate (40%) compared to historical control (20%, P = .038).[18] Increased frequency of AFP-specific T cells were detected in the peripheral blood of stage III/IV HCC patients after injection of AFP peptide–pulsed DC.[19]

Finally, a recent phase II trial tested the use of formalin-fixed autologous tumor plus granulocyte colony-stimulating factor (G-CSF, Neupogen) and IL-2 after curative resection. The 19 patients who received the vaccine treatment showed a significantly lower recurrence risk, longer time to recurrence, and improved recurrence-free survival rate (all P = .003), as well as greater overall survival rate (P = .01), compared with the 22 patients who received no adjuvant therapy. [20]

Conclusions
In conclusion, these data have revealed that adoptive transfer effector cells and tumor-derived vaccines have an impact on recurrence and survival in postsurgical HCC patients. Researchers need to generate further clinical trials of adjuvant immunotherapy to demonstrate the benefit of these strategies with or without novel kinase inhibitors in preventing recurrence of HCC after liver transplantation.

References:

1. Llovet JM, Burroughs A, Bruix J: Hepatocellular carcinoma. Lancet 362:1907-1917, 2003.
2. Okuda K: Hepatocellular carcinoma. J Hepatol 32:225-237, 2000.
3. Schlitt HJ, Neipp M, Weimann A, et al: Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation. J Clin Oncol 17:324-331, 1999.
4. Ceriello A, Mezza F, Cozzolino S, et al: Role of immunosuppression in recurrence after liver transplantation for diethylnitrosamine-induced tumors in rats. Transpl Int 7(suppl 1):S204-S207, 1994.
5. Freise CE, Ferrell L, Liu T, et al: Effect of systemic cyclosporine on tumor recurrence after liver transplantation in a model of hepatocellular carcinoma. Transplantation 67:510-513, 1999.
6. Vander Borght S, Komuta M, Libbrecht L, et al: Expression of multidrug resistance-associated protein 1 in hepatocellular carcinoma is associated with a more aggressive tumour phenotype and may reflect a progenitor cell origin. Liver Int 28:1370-1380, 2008.
7. Yoo BK, Gredler R, Vozhilla N, et al: Identification of genes conferring resistance to 5-fluorouracil. Proc Natl Acad Sci U S A 106:
12938-12943, 2009.
8. Lee JO, Kim DY, Lim JH, et al: Palliative chemotherapy for patients with recurrent hepatocellular carcinoma after liver transplantation. J Gastroenterol Hepatol 24:800-805, 2009.
9. Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378-390, 2008.
10. Kawata A, Une Y, Hosokawa M, et al: Tumor-infiltrating lymphocytes and prognosis of hepatocellular carcinoma. Jpn J Clin Oncol 22:256-263, 1992.
11. Oquinena S, Guillen-Grima F, Inarrairaegui M, et al: Spontaneous regression of hepatocellular carcinoma: A systematic review. Eur J Gastroenterol Hepatol 21:254-257, 2009.
12. Park HS, Jang KY, Kim YK, et al: Hepatocellular carcinoma with massive lymphoid infiltration: A regressing phenomenon? Pathol Res Pract 205:648-652, 2009.
13. Butterfield LH: Immunotherapeutic strategies for hepatocellular carcinoma. Gastroenterology 127:S232-S241, 2004.
14. Chiriva-Internati M, Grizzi F, Wachtel MS, et al: Biological treatment for liver tumor and new potential biomarkers. Dig Dis Sci 53:836-843, 2008.
15. Zerbini A, Pilli M, Ferrari C, et al: Is there a role for immunotherapy in hepatocellular carcinoma? Dig Liver Dis 38:221-225, 2006.
16. Peng BG, Liang LJ, He Q, et al: Tumor vaccine against recurrence of hepatocellular carcinoma. World J Gastroenterol 11:700-704, 2005.
17. Takayama T, Sekine T, Makuuchi M, et al: Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: A randomised trial. Lancet 356:802-807, 2000.
18. Stift A, Friedl J, Dubsky P, et al: Dendritic cell-based vaccination in solid cancer. J Clin Oncol 21:135-142, 2003.
19. Butterfield LH, Ribas A, Dissette VB, et al: A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res 12:2817-2825, 2006.
20. Kuang M, Peng BG, Lu MD, et al: Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin Cancer Res 10:1574-1579, 2004.