Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: A randomised trial

Tadatoshi Takayama, Teruaki Sekine, Masatoshi Makuuchi, Susumu Yamasaki, Tomoo Kosuge, Junji Yamamoto, Kazuaki Shimada, Michiie Sakamoto, Setsuo Hirohashi, Yasuo Ohashi, Tadao Kakizoe

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Abstract

Background: Postsurgical recurrence of hepatocellular carcinoma (HCC) is frequent and fatal. Adoptive immunotherapy is active against HCC. We assessed whether postoperative immunotherapy could lower the frequency of recurrence. Methods: Between 1992 and 1995, we did a randomised trial in which 150 patients who had undergone curative resection for HCC were assigned adoptive immunotherapy (n=76) or no adjuvant treatment (n=74). Autologous lymphocytes activated vitro with recombinant interleukin-2 and antibody to CD3 were infused five times during the first 6 months. Primary endpoints were time to first recurrence and recurrence-free survival and analyses were by intention to treat. Findings: 76 patients received 370 (97%) of 380 scheduled lymphocyte infusions (mean cell number per patient 7.1x1010 [SD 2.1]; CD3 and HLA-DR cells 78% [16]), and none had grade 3 or 4 adverse events. After a median follow-up of 4.4 years (range 0.2-6.7), adoptive immunotherapy decreased the frequency of recurrence by 18% compared with controls (45% [59] vs 57% [77]) and reduced the risk of recurrence by 41% (95% Cl 12-60, p=0.01). Time to first recurrence in the immunotherapy group was significantly longer than that in the control group (48% [37-59] vs 33% [22-43] at 3 years, 38% [22-54] vs 22% [11-34] at 5 years; p=0.008). The immunotherapy group had significantly longer recurrence-free survival (p=0.01) and disease-specific survival (p=0.04) than the control group. Overall survival did not differ significantly between groups (p=0.09). Interpretation: Adoptive immunotherapy is a safe, feasible treatment that can lower recurrence and improve recurrence-free outcomes after surgery for HCC.

Original languageEnglish
Pages (from-to)802-807
Number of pages6
JournalLancet
Volume356
Issue number9232
DOIs
Publication statusPublished - 2000 Sep 2
Externally publishedYes

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Adoptive Immunotherapy
Hepatocellular Carcinoma
Recurrence
Immunotherapy
Survival
Lymphocytes
Control Groups
HLA-DR Antigens
Survival Analysis
Interleukin-2
Cell Count

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Takayama, T., Sekine, T., Makuuchi, M., Yamasaki, S., Kosuge, T., Yamamoto, J., ... Kakizoe, T. (2000). Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: A randomised trial. Lancet, 356(9232), 802-807. https://doi.org/10.1016/S0140-6736(00)02654-4

Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma : A randomised trial. / Takayama, Tadatoshi; Sekine, Teruaki; Makuuchi, Masatoshi; Yamasaki, Susumu; Kosuge, Tomoo; Yamamoto, Junji; Shimada, Kazuaki; Sakamoto, Michiie; Hirohashi, Setsuo; Ohashi, Yasuo; Kakizoe, Tadao.

In: Lancet, Vol. 356, No. 9232, 02.09.2000, p. 802-807.

Research output: Contribution to journalArticle

Takayama, T, Sekine, T, Makuuchi, M, Yamasaki, S, Kosuge, T, Yamamoto, J, Shimada, K, Sakamoto, M, Hirohashi, S, Ohashi, Y & Kakizoe, T 2000, 'Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: A randomised trial', Lancet, vol. 356, no. 9232, pp. 802-807. https://doi.org/10.1016/S0140-6736(00)02654-4
Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: A randomised trial. Lancet. 2000 Sep 2;356(9232):802-807. https://doi.org/10.1016/S0140-6736(00)02654-4
Takayama, Tadatoshi ; Sekine, Teruaki ; Makuuchi, Masatoshi ; Yamasaki, Susumu ; Kosuge, Tomoo ; Yamamoto, Junji ; Shimada, Kazuaki ; Sakamoto, Michiie ; Hirohashi, Setsuo ; Ohashi, Yasuo ; Kakizoe, Tadao. / Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma : A randomised trial. In: Lancet. 2000 ; Vol. 356, No. 9232. pp. 802-807.
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T1 - Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma

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AU - Takayama, Tadatoshi

AU - Sekine, Teruaki

AU - Makuuchi, Masatoshi

AU - Yamasaki, Susumu

AU - Kosuge, Tomoo

AU - Yamamoto, Junji

AU - Shimada, Kazuaki

AU - Sakamoto, Michiie

AU - Hirohashi, Setsuo

AU - Ohashi, Yasuo

AU - Kakizoe, Tadao

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N2 - Background: Postsurgical recurrence of hepatocellular carcinoma (HCC) is frequent and fatal. Adoptive immunotherapy is active against HCC. We assessed whether postoperative immunotherapy could lower the frequency of recurrence. Methods: Between 1992 and 1995, we did a randomised trial in which 150 patients who had undergone curative resection for HCC were assigned adoptive immunotherapy (n=76) or no adjuvant treatment (n=74). Autologous lymphocytes activated vitro with recombinant interleukin-2 and antibody to CD3 were infused five times during the first 6 months. Primary endpoints were time to first recurrence and recurrence-free survival and analyses were by intention to treat. Findings: 76 patients received 370 (97%) of 380 scheduled lymphocyte infusions (mean cell number per patient 7.1x1010 [SD 2.1]; CD3 and HLA-DR cells 78% [16]), and none had grade 3 or 4 adverse events. After a median follow-up of 4.4 years (range 0.2-6.7), adoptive immunotherapy decreased the frequency of recurrence by 18% compared with controls (45% [59] vs 57% [77]) and reduced the risk of recurrence by 41% (95% Cl 12-60, p=0.01). Time to first recurrence in the immunotherapy group was significantly longer than that in the control group (48% [37-59] vs 33% [22-43] at 3 years, 38% [22-54] vs 22% [11-34] at 5 years; p=0.008). The immunotherapy group had significantly longer recurrence-free survival (p=0.01) and disease-specific survival (p=0.04) than the control group. Overall survival did not differ significantly between groups (p=0.09). Interpretation: Adoptive immunotherapy is a safe, feasible treatment that can lower recurrence and improve recurrence-free outcomes after surgery for HCC.

AB - Background: Postsurgical recurrence of hepatocellular carcinoma (HCC) is frequent and fatal. Adoptive immunotherapy is active against HCC. We assessed whether postoperative immunotherapy could lower the frequency of recurrence. Methods: Between 1992 and 1995, we did a randomised trial in which 150 patients who had undergone curative resection for HCC were assigned adoptive immunotherapy (n=76) or no adjuvant treatment (n=74). Autologous lymphocytes activated vitro with recombinant interleukin-2 and antibody to CD3 were infused five times during the first 6 months. Primary endpoints were time to first recurrence and recurrence-free survival and analyses were by intention to treat. Findings: 76 patients received 370 (97%) of 380 scheduled lymphocyte infusions (mean cell number per patient 7.1x1010 [SD 2.1]; CD3 and HLA-DR cells 78% [16]), and none had grade 3 or 4 adverse events. After a median follow-up of 4.4 years (range 0.2-6.7), adoptive immunotherapy decreased the frequency of recurrence by 18% compared with controls (45% [59] vs 57% [77]) and reduced the risk of recurrence by 41% (95% Cl 12-60, p=0.01). Time to first recurrence in the immunotherapy group was significantly longer than that in the control group (48% [37-59] vs 33% [22-43] at 3 years, 38% [22-54] vs 22% [11-34] at 5 years; p=0.008). The immunotherapy group had significantly longer recurrence-free survival (p=0.01) and disease-specific survival (p=0.04) than the control group. Overall survival did not differ significantly between groups (p=0.09). Interpretation: Adoptive immunotherapy is a safe, feasible treatment that can lower recurrence and improve recurrence-free outcomes after surgery for HCC.

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