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Liver transplantation for treatment of hepatocellular carcinoma (HCC) has evolved over the course of the last 2 decades. Surgical resection, frequently impossible due to poor baseline hepatic function and the lack of hepatic reserve, is associated with a high rate of recurrence within 3-5 years of resection. Liver transplantation, thought to represent the ultimate resection, was met with great initial enthusiasm. However, episodes of recurrence made it clear that residual tumor was often present. Trials of pretransplant, peritransplant, and posttransplant adjunctive treatments were also met with enthusiasm; however, small study populations and brief follow-up made definitive conclusions difficult.

The landmark paper that changed the standard of practice was published in 1996.1 Tumor burden clearly had an effect on rates of recurrence and survival. What has become known as the Milan criteria is the standard for inclusion and exclusion. One tumor nodule no greater than 5 cm in diameter or up to 3 nodules, none bigger than 3 cm in diameter, is the standard that transplant centers follow, at least in the United States. Staying within these criteria is associated with survival rates of 70% at 5 years, with similar rates of disease-free survival. These remarkable rates led to patients with the diagnosis of HCC being given higher priority on the transplant waiting list. Initially, this led to 23% of all liver transplants being performed for HCC. A subsequent revision of the priority points lowered the priority, though HCC remains a common indication for transplantation. An additional study suggests these criteria could be extended, without changing the rates of survival or disease recurrence.2

Transplantation for HCC has been associated with excellent survival rates; however, the incidence of recurrent disease and the risk of progressive disease prior to the availability of a suitable donor organ led to further efforts at decreasing tumor load before transplant and destroying micrometastases during and after the transplant. Transarterial chemoembolization (TACE) is used at many centers in an attempt to slow tumor growth and prevent disease progression.3, 4 Strong opinions exist as to the efficacy of this treatment, though definitive studies showing prolonged survival are lacking.

In this issue of HEPATOLOGY, Yeng and colleagues present intriguing data on the use of a murine monoclonal antibody labeled with I131 against Hab18G/CD147, a common antigen seen in hepatocellular carcinoma and associated with progressive disease, in the treatment of advanced HCC following transplantation.5 Hab18G/CD147 is commonly expressed on HCC cells,6, 7 with positive immunohistochemical staining in 75% of samples in one study, without evidence of staining in normal hepatic tissue.8 By changing the microenvironment, it was found that the antigen appears to be related to the invasive potential of the tumor. Binding of the antibody to the antigen slows disease progression, an effect magnified by the delivery of the radionuclide iodine-131.9 Sixty patients were randomized into groups receiving 3 infusions of the study drug or placebo following transplantation. Patients treated with the radiolabeled antibody had no increased rates of adverse events. Of note, the patients selected for the study all had stage 3 (40%) or 4 (60%) HCC, beyond the standard criteria routinely used in most U.S. centers.

In spite of the advanced stages of HCC used in this study, patient and disease-free survival were improved in the treatment group. Survival improved by 20% in the treatment group at 1 year, whereas the recurrence rate decreased by 30%. Though the results were not equal to survival and disease-free survival rates seen in patients who underwent transplantation within the Milan criteria, the improvement in a group of patients previously associated with dismal outcomes is remarkable.

On the basis of these results, should all transplant centers consider using this agent in their patients with HCC? Such a recommendation is difficult to make without answering additional questions. Additional studies with larger numbers must be completed. A more heterogenous population should be studied as well. For example, do patients with underlying liver disease other than hepatitis B respond as well as this population? Do patients without positive immunohistochemical stains for Hab18G/CD147 have a similarly high response rate? Finally, is there a difference in response rates in patients with less extensive disease? Studies on the timing of administration are needed. Specifically, if neutralization of the antigen is key, why not give the drug preoperatively and/or perioperatively with the hope of wiping out micrometastases earlier rather than after they have had a chance to spread in the face of high-dose immunosuppression in the posttransplant period? Could even greater efficacy be demonstrated if this agent was given in concert with TACE, a sort of “one-two punch” with TACE taking out large numbers of cells and the radiolabeled antibody working on those cells outside the region affected by TACE?

The study does confirm what studies have shown previously: patients with advanced HCC do not do well after liver transplantation. The disease recurs and patients die. This leads to screening through the previously mentioned Milan criteria and the markedly improved overall rates of survival now seen in transplant recipients with this disease. However, could we decrease recurrence rates and patient mortality rates even further if this agent was used? Perhaps survival and disease-free survival rates would increase even further in patients chosen for transplantation under the Milan criteria or the extended criteria proposed by the UCSF group. These variations of the study clearly need to be explored as better ways to treat and cure patients with this increasingly prevalent disease are sought.

This study raises additional concerns for another reason. Questions have been asked regarding the source of donor organs in China. In July 2006, the World Transplant Congress (WTC) in Boston brought together the American Society of Transplantation, the American Society of Transplant Surgeons, and The Transplantation Society for the largest meeting of its kind. However, the unique nature of the WTC was not limited to the combined efforts of the 3 societies. Protesters stood outside the Hynes Convention Center on Boylston Street, raising unsettling allegations.

Falun Gong is a traditional Chinese spiritual discipline based on truth, compassion, and tolerance. Banned in China in 1999, many of its followers have been detained or imprisoned. Those affiliated with Falun Gong have accused the Chinese government of killing those imprisoned, with their organs, bones, and tissues allegedly being transplanted. Although passionately and graphically described, there has been little in the way of documentation of such atrocities.

Should we condone such activity, if it is occurring? Of course not. In fact, the rights of the donor should always be held in the highest regard. In its Ethics Statement,10 the American Society of Transplantation clearly states the following: “All decisions to donate must be made freely and without coercion or exploitation of any sort including financial or otherwise.” Furthermore, “To respect a person's dignity and free choice, donors must not be viewed primarily as a resource for transplants.” Regardless of where a transplant occurs, these principles must be upheld.

Allegations such as those listed must be carefully considered as a manuscript is considered for inclusion in HEPATOLOGY. As we review scientific manuscripts, the principles of the World Medical Association's Declaration of Helsinki must be in place.11 In particular, “It is the duty of the physician to protect the life, health, privacy, and dignity of the human subject.” One could argue that the interests of the human subjects in this study were protected. However, solid organ transplantation involves more than one human subject. An organ donor is necessary for the “gift of life” to occur. If any of the organs were obtained in a means that failed to preserve the dignity and free choice of the donor, the principles of the Declaration of Helsinki have not been upheld and the manuscript should be rejected. However, the authors assured the editor that the study drug was registered with the State Food and Drug Administration of China and that the study was approved by the institutional Medical Ethics Committee, the equivalent of an institutional review board. Furthermore, the authors also stated donated organs were not obtained from executed prisoners and the appropriate consent was obtained from the donor or the next of kin, when the donor was unable to give consent due to the circumstances related to their death. Based on these reassurances, the manuscript was accepted for publication.

What reassurance do we, as a transplant community, have with regard to the standard of practice in China? On November 14, 2006, the National Summit of Clinical Application and Management of Human Organ Transplantation met in Guangzhou, the capital of South China's Guangdong province. A statement was delivered from the Committee on Clinical Application of Human Organ Transplantation of China, a group that met the previous day. In short, the committee stated that human organ transplantation will be legally developed, with protections for the rights of donors and patients.

The high prevalence of chronic viral hepatitis and its complications makes China a fertile ground for the study of liver transplantation and its complications. Although allegations must be considered and principles of human rights upheld, we should be slow to judge the actions of others without knowing the facts. If organs from executed prisoners are being used, or there is any evidence the principles of the Declaration of Helsinki have not been followed, the practice should be decried and the manuscript rejected. However, the actions of some do not necessarily imply that all members of a country follow the same deplorable practice. All submissions must be judged on their own merit.

Submissions from China to scientific meetings and journals will continue to increase. Engaging in discussion at annual meetings and invited lectures develops relationships and spreads information related to scientific investigation and clinical practice. Educating clinical trainees from abroad leads to dissemination of practice patterns once the trainee returns home. Let us embrace our Chinese colleagues and their studies with the same attention to critical analysis we apply to ourselves.

References

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  2. References
  • 1
    Mazzaferro V, Regalio E, Doci R, Andreola S, Pulvirneti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693699.
  • 2
    Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact patient survival. HEPATOLOGY 2001; 33: 13941403.
  • 3
    Yao FY, Hirose R, LaBerge JM, Davern TJ, Bass NM, Kerlan RK, et al. A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transpl 2005; 11: 15051514.
  • 4
    Perez Saborido B, Meneu JC, Morenao E, Garcia I, Moreno A, Fundora Y, et al. Is transarterial chemoembolization necessary before liver transplantation for hepatocellular carcinoma? Am J Surg 2005; 190: 383387.
  • 5
    Xu J, Shen Z, Chin X, Zhang Q, Bian H, Zhu P, et al. A randomized controlled trial of LICARTIN for prevention of hepatoma recurrence after liver transplantation. HEPATOLOGY 2007; 45: 269276.
  • 6
    Toole BP. Emmprin (CD147), a cell surface regulator of matrix metalloproteinase production and function. Curr Top Dev Biol 2003; 54: 371389.
  • 7
    Chen ZN, Shang P, Li Y, Qian AR, Zhu P, Xing JL, inventors; NTD Patent and Trademark Agency, Beijing office, assignee. HAb18G/CD147, its agonist and application. Chinese patent ZL01131735.3, 2001 Sep 28;PCT international patent W002/094875. 2002 May 27.
  • 8
    Chen ZN, Xing JL, Zhang SH, inventors; NTD Patent & Trademark Agency, Beijing office, assignee. Anti-human hepatoma monoclonal antibody HAb18 light/heavy chain variable region gene, and use thereof. Chinese patent ZL02114471.0, 2002 March 15;PCT international patent W003/078469. 2003 March 17.
  • 9
    Chen Z, Mi L, Xu J, Song F, Zhang Q, Zhang Z, et al. Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical phase I/II trials. Int J Radiat Oncol Biol Phys 2006; 65: 435444.
  • 10
    American Society of Transplantation. Statement on Ethics. http://a-s-t.org/about/generalethics.htm; accessed December 26, 2006.
  • 11
    The World Medical Association. Policy. http://www.wma.net/e/policy/b3.html; accessed December 30, 2006.