Adjuvant Immunotherapy Prolongs Disease-free Survival in Hepatocellular Cancer Patients
ABSTRACT & COMMENTARY
Synopsis: Hepatocellular carcinoma has proven refractory to radiation and chemotherapy approaches, but recent phase II trials have elicited some hope for immunotherapy. In this report from Japan, patients without apparent residual disease after initial surgical resection were randomized to receive in vitro activated autologous lymphocytes in an adjuvant immunotherapy trial. This approach reduced tumor recurrence by 41% and increased the disease-free interval, on average, by more than a year. Thus, this nonspecific immunotherapy resulted in improved outcomes for patients treated in the adjuvant setting.
Source: Takayama T, et al. Lancet 2000;356:802-807.
Hepatocellular carcinoma is the number one cause of cancer-related death worldwide. Currently, the only curative approach is resection with or without hepatic transplantation, but unfortunately, even after early detection and curative-intent resection, recurrence and death are likely outcomes.1 Chemo- or radiation therapies, even with novel approaches, such as chemoembolization, have not improved survival.2 Immunotherapy has shown some promise in this disease. In phase II studies, for example, the infusion of an expanded population of autologous lymphocytes has resulted in demonstrable responses in approximately 20% of patients.3,4 In the current research, Takayama and colleagues from the National Cancer Center Hospital in Tokyo, report the results of a randomized trial in which 150 patients who had undergone curative-intent resection for hepatocellular carcinoma were randomized to receive either adoptive immunotherapy (as below) or no adjuvant therapy.
The adoptive immunotherapy program chosen was innovative inasmuch as it involved the in vitro expansion of a lymphocyte population that was initially harvested and cultured from a 100 cc blood donation prior to surgery (no leukopheresis required). Lymphocytes from the blood sample were isolated and expanded in number by the addition in culture of interleukin-2 and antibody to the cell surface CD3 molecule (OKT3). These cells were infused five times during the first six months after hepatic surgery. There was no grade 3 or 4 toxicity observed, and 97% of all planned infusions were administered.
After a median follow-up of 4.4 years, those that had received the adoptive immunotherapy had a reduced frequency of recurrence compared with controls (59% vs 77% [95% CI 12-60; P = 0.01]). The median time to first recurrence was also significantly longer for the treatment group (2.8 years vs 1.6 years for the controls; P = 0.008). Thus, compared with no adjuvant therapy, adoptive immunotherapy significantly lowered the risks of overall recurrence by 41% (P = 0.01), early recurrence (i.e., recurrence during the first 2 years after hepatic resection) by 51% (P = 0.005), and extensive recurrence (i.e., more than 5 tumors or any tumor with vascular invasion) by 56% (P = 0.03). Of those treated with immunotherapy, 21 (28%) died during the study period, whereas 31 (42%) of the control group died during the same period, but this difference in overall survival did not reach a level of statistical significance (P = 0.09).
COMMENT by William B. Ershler, MD
This is an encouraging report about the application of biological therapy to a disease that has proven resistant to all but surgical approaches. Adoptive immunotherapy with cytokine-activated lymphocytes has been of modestly demonstrable benefit in the management of melanoma and renal carcinoma5,6 and now, possibly, hepatocellular carcinoma may be added to the list. This report, however, should be considered a springboard, inasmuch as the approach (autologous, nonspecifically stimulated lymphocytes) is a broad-stroke effort, and hopefully future refinements will be more (antigen) specific and thereby more effective. Also, the response to adoptive immunotherapy raises the possibility that vaccine approaches might also be developed, as has been an emphasis in melanoma immunotherapy research.
The current approach is cumbersome and expensive; certainly not the answer for the huge problem of hepatocellular cancer worldwide. In this regard, the emphasis on prevention, particularly by hepatitis B, and hopefully someday hepatitis C vaccine as well as reduction in aflotoxin exposure are efforts that have already reduced hepatocellular cancer incidence6 and, on the large scale, are much more likely to reduce the devastating effect of this disease.
References
1. Lai ECS, et al. Ann Surg 1995;221:291-298.
2. Schaefer DF, et al. Lancet 1999;353:1253-1257.
3. Takayama T, et al. Cancer 1991;68:2391-2396.
4. Aruga A, et al. Int J Cancer 1991;49:19-24.
5. Rosenberg SA, et al. N Engl J Med 1987;316:889-897.
6. Osband ME, et al. Lancet 1990;335:994-998.
7. Chang MH, et al. N Engl J Med 1997;337:1855-1859.
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