|Year : 2018 | Volume
| Issue : 4 | Page : 807-814
A meta-analysis of adoptive immunotherapy in postoperative hepatocellular carcinoma
Hui Zhao1, Min Zheng2, Kun Wang1, Lianmin Wang1, Haiyu He3, Meilian Wang3, Yanmei Shi3, Songquan Huang1, Fengming Ji1, Xiao Li1, Hong Zhu1, Lin Wang1, Xiaowen Zhang1, Xueyang Shi1, Songling Zhao1, Bimang Fu1, Tao Wu1
1 Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
2 Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
3 Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
|Date of Web Publication||27-Jun-2018|
Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Kunming Medical University, No. 374, Dianmian Road, Kunming 650101, Yunnan
Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Kunming Medical University, No. 374, Dianmian Road, Kunming 650101, Yunnan
Source of Support: None, Conflict of Interest: None
Background: Adoptive immunotherapy (AIT) has been adopted as an adjuvant treatment for hepatocellular carcinoma (HCC) patients after curative therapy. However, the outcomes of AIT remain controversial.
Purpose: The purpose of this study is to analyze the safety and efficacy of AIT with the recurrence rate and mortality.
Materials and Methods: We identified eight randomized controlled trials (RCTs) that adopted AIT to HCC after curative treatments. A meta-analysis was carried out to assess the recurrence rate and mortality.
Results: Eight RCTs with 964 patients were included in the study. The overall analysis showed that AIT treatment can not only decrease the 1-year (risk ratio [RR] =0.59, 95% confidence interval [95% CI] = 0.48–0.72, P < 0.00001), 2-year (RR = 0.69, 95% CI = 0.60–0.79, P < 0.00001), and 3-year (RR = 0.82, 95% CI = 0.74–091, P = 0.0001) recurrence, but also decrease the 1-year (RR = 0.43, 95% CI = 0.30–0.62, P = 0.00001), 2-year (RR = 0.56, 95% CI = 0.46–0.74, P < 0.00001), and 3-year (RR = 0.85, 95% CI = 0.73–0.99, P = 0.03) mortality. The results also indicate that the group of lymphokine-activated killer (LAK) cells showed lower pooled RR values compared to the group of cytokine-induced killer cells among every subgroups. However, the AIT treatment failed to affect the 5-year recurrence rate and mortality (P > 0.05).
Conclusions: This review provides available evidences that AIT, especially the treatment of LAK, can be used to decrease the early recurrence and mortality of postoperative HCC but may not the long term.
Keywords: Adoptive immunotherapy, cytokine-induced killer, hepatocellular carcinoma, lymphokine-activated killer
|How to cite this article:|
Zhao H, Zheng M, Wang K, Wang L, He H, Wang M, Shi Y, Huang S, Ji F, Li X, Zhu H, Wang L, Zhang X, Shi X, Zhao S, Fu B, Wu T. A meta-analysis of adoptive immunotherapy in postoperative hepatocellular carcinoma. J Can Res Ther 2018;14:807-14
|How to cite this URL:|
Zhao H, Zheng M, Wang K, Wang L, He H, Wang M, Shi Y, Huang S, Ji F, Li X, Zhu H, Wang L, Zhang X, Shi X, Zhao S, Fu B, Wu T. A meta-analysis of adoptive immunotherapy in postoperative hepatocellular carcinoma. J Can Res Ther [serial online] 2018 [cited 2019 Aug 26];14:807-14. Available from: http://www.cancerjournal.net/text.asp?2018/14/4/807/235101
Hui Zhao, Min Zheng and Kun Wang contributed equally to this work.
| > Introduction|| |
Hepatocellular carcinoma (HCC) is the most common type of all liver cancers, and the occurrence of HCC increased by annually from globally. Now, it is considered the third cause of deaths owing to cancer around the world. Although the now radical treatment, such as liver resection and radiofrequency ablation (RFA), can help improve the 5-year survival rates to 37%,, the recurrence of HCC is up to 25%. These data indicate that patients with HCC need for effective adjuvant therapies to improve the outcomes after curative treatment.
The adoptive immunotherapy (AIT) can improve the outcomes of HCC patients by activating and utilizing the immune system to struggle with the cancer cells. Two main strategies are available now for AIT and consist of lymphokine-activated killer (LAK) cells and cytokine-induced killer (CIK) cells. Due to the advantage that avoids the limitation caused by major histocompatibility complex, AIT has been widely used in the postoperative HCC from the first reported in the early 1980s., However, there is still a controversy about the value of AIT for HCC patients after curative treatment, especially in the long-term clinical outcomes.,,, Hence, we performed this meta-analysis with published randomized controlled trials (RCTs) to evaluate the efficacy of AIT in postoperative HCC.
| > Materials and Methods|| |
Literature search strategy
The relevant studies were searched in PubMed, Embase, the Cochrane Central Register of Controlled Trials, Science Citation Index, the Chinese BioMedical Literature Database, and the American Society of Clinical Oncology Annual Scientific Meeting proceedings. The keywords were as follows: “liver tumor” or “liver cancer” or “hepatic cancer” or “hepatic tumor” or “hepatocellular carcinoma” and “hepatectomy” or “hepatic resection” or “operation” or “liver resection” and “immunotherapy” or “cytokine-induced killer cells” or “lymphokine-activated killer cells” or “postoperative” or “interleukin-2.” To avoid missing relevant studies, no language restriction and no filter were applied in the search strategy.
The research included in this systematic review satisfied the following criteria: (a) the RCTs comparing patients receiving the immunotherapy or not for the patients with HCC; (b) all the patients received curative treatment before immunotherapy; (c) the patients received otherwise similar treatments both in AIT and non-AIT arms; and (d) the study shows estimating risk ratios (RRs) with 95% confidence intervals (95% CIs). The curative therapies include RFA, percutaneous ethanol injection, and liver resection and not include the liver transplantation.
The studies were excluded if the patients involved were liver metastases and advanced or unresectable HCC. The summary publication or conference abstracts were also excluded.
Data extraction and quality assessment
Two authors (Hui zhao and Min zheng) independently screened the original literature identified on the standard form, and the discrepancies were arbitrated by a third author. The following information was extracted from each publications: author details, country, study design, sample size, surgery method, immunotherapy regimen, hepatitis B/C virus (HBV/HCV), cirrhosis rate, Child–Pugh class, and outcomes (positive and negative findings).
This systematic review was performed based on the Quality of Reporting of Meta-analyses statement. Two authors (Hui zhao and Kun wang) independently evaluate the methods and results of all included RCT publications based on the method of randomization, allocation sequence generation, allocation concealment, blinding of outcome assessors, description of protocol deviations, withdrawals, and dropouts.
Review Manager 5.3 (The Cochrane Collaboration, Oxford, England) was used to analyze the data extracted from all included articles. The estimated effect measures for dichotomous outcomes were RR with 95% CI based on the Mantel–Haenszel method, and the point estimates of RR were considered statistically significant when P < 0.05. The homogeneity between studies was determined using Chi-square test, with significance set at P = 0.05. The statistical heterogeneity was evaluated using I2 (I2 = 25%, 50%, and 75% indicate low, moderate, and high heterogeneity, respectively). Meta-analysis was performed with a random-effects model if substantial heterogeneity according to the threshold of I2 was found among all included publications. Otherwise, the analysis was performed with a fixed-effects model. Publication bias was exhibited with funnel plots.
| > Results|| |
Description of included trials
Our search identified a total of 925 articles, which decreased to 463 after 462 duplicates or clearly irrelevant references were removed. The remaining 17 articles screened with the titles, and abstracts were evaluated for analysis at full-text level. According to the inclusion criterion, eight articles (three studies focusing on the effect of AIT in patients with advanced HCC, one focusing on different postoperative immunotherapy methods, two articles were repeated studies, and two cohort studies) were excluded from the study. At last, eight RCTs ,,,,,,, including 964 patients were included in the meta-analysis [Figure 1] and [Table 1].
All patients involved in studies were Asian, and five trials were performed in China, one trial was performed in Korea, and two trials were performed in Japan. All the patients involved had received hepatic resection before AIT. Five trials (685 patients) adopted CIK as AIT, two trials (85 patients) adopted CIK plus interleukin-2 (IL-2) as AIT, and one trial adopted transcatheter arterial chemoembolization (TACE) and LAK plus IL-2. The messages of all studies are summarized in [Table 1].
Efficacy assessment of adoptive immunotherapy
Eight RCT studies retorted the information of 1-year recurrence and mortality, seven RCT studies provided the information of 2-year and 3-year recurrence and mortality, and four RCT studies provided the data of 5-year recurrence and mortality. Our meta-analysis indicated that immunotherapy combined with curative treatment had a significant benefit in HCC recurrence compared with the only curative treatment according to 1-year (RR = 0.59; 95% CI = 0.48–0.72; P < 0.00001, I2 = 0%), 2-year (RR = 0.69; 95% CI = 0.60–0.79; P < 0.00001, I2 = 16%), and 3-year recurrence (RR = 0.82; 95% CI = 0.74–0.91; P = 0.0001, I2 = 29%) [Figure 2]. In addition, the postoperative HCC patients received the treatment of LAK showed better clinical outcomes in HCC recurrence than the treatment of CIK in early prognosis according to 1-year recurrence by CIK (RR = 0.62; 95% CI = 0.50–0.76; P < 0.00001, I2 = 0%), 2-year recurrence by CIK (RR = 0.70; 95% CI = 0.61–0.81; P < 0.00001, I2 = 30%), and 3-year recurrence by CIK (RR = 0.84; 95% CI = 0.75–0.93; P = 0.0008, I2 = 40%) and 1-year recurrence by LAK (RR = 0.42; 95% CI = 0.24–0.75; P = 0.003, I2 = 17%), 2-year recurrence by LAK (RR = 0.53; 95% CI = 0.30–0.93; P = 0.03, I2 = 0%), and 3-year recurrence by LAK (RR = 0.67; 95% CI = 0.47–0.95; P = 0.02, I2 = 0%) [Table 2]. However, there is no significant difference for the 5-year recurrence between patients receiving immunotherapy after curative treatment than receiving curative treatment only (P > 0.05). The corresponding pooled RR was estimated at 0.94 (95% CI = 0.87–1.02; P = 0.13, I2 = 0%). Therefore, the benefits of AIT for HCC patients after curative treatment mainly existed in early stages.
|Figure 2: Comparison of recurrence rate between adjuvant adoptive immunotherapy and nonimmunotherapy postoperation|
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|Table 2: Summary of pooled risk ratios of clinical prognosis by adjuvant immunotherapy methods|
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The benefits of AIT for HCC patients after curative treatment were also proved on mortality. The meta-analysis indicated that the AIT group shows a lower 1-year (RR = 0.43; 95% CI = 0.30–0.62; P < 0.00001, I2 = 0%), 2-year (RR = 0.56; 95% CI = 0.46–0.74; P < 0.00001, I2 = 0%), and 3-year mortality (RR = 0.85; 95% CI = 0.73–0.99; P = 0.03, I2 = 57%). Moreover, the LAK subgroup showed lower mortality compared to the subgroup of CIK according to the 1-year mortality by CIK (RR = 0.46; 95% CI = 0.32–0.66; P < 0.0001, I2 = 11%), 2-year mortality by CIK (RR = 0.60; 95% CI = 0.47–0.77; P < 0.0001, I2 = 11%), and 3-year mortality by CIK (RR = 0.87; 95% CI = 0.75–1.02; P < 0.0001, I2 = 67%) and 1-year mortality by LAK (RR = 0.14; 95% CI = 0.02–1.10; P = 0.06, I2 = 0%), 2-year mortality by LAK (RR = 0.36; 95% CI = 0.13–1.02; P = 0.05, I2 = 0%), and 3-year mortality by LAK (RR = 0.61; 95% CI = 0.35–1.07; P = 0.08, I2 = 0%) [Table 2]. However, there is no significant difference for the 5-year mortality between patients receiving immunotherapy after curative treatment than receiving curative treatment only (P > 0.05) [Figure 3].
|Figure 3: Comparison of mortality between adjuvant adoptive immunotherapy and nonimmunotherapy postoperation |
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Safety assessment of adoptive immunotherapy
None of the eight RCTs included reported serious adverse events caused by AIT. The common AIT agent-related adverse events include fever and chills. Only five patients have not fulfilled AIT for the side effects of persistent fever. Other patients' fever in this meta-analysis had been controlled easily with symptomatic therapies. There are also several rare adverse events, such as myalgia, headache, dizziness, fatigue, and nausea, with the Grade of 1 or 2. None of the patients delay or stop treatment because of the adverse events except for the five patients mentioned above. All eight articles included had not reported hepatic deterioration, infection, or autoimmune disorder.
Assessment of publication bias
Funnel plots of the eight studies were performed to evaluate the publication bias in this meta-analysis, and the symmetrical of the funnel plots indicates minimal risk of publication bias [Figure 4] and [Figure 5].
|Figure 4: Funnel plots of adjuvant adoptive immunotherapy and recurrence rate|
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| > Discussion|| |
Our meta-analysis suggests that AIT is a safe and efficient treatment strategy that can improve significantly the clinical prognosis (recurrence and survival rate) for postoperative HCC in early stage (<3 years) but not in late stage (5 years). This may mean that AIT may hold a powerful destroy role on tumor cells in a short period but may have no effect in the long term. Hence, the underlying mechanism of AIT in postoperative HThe reason for this is that the immune response is significantly suppressed in HCC patients and tumor cells could escape the host immune surveillance, which make the tumor is difficult to cure. The cellular immunity plays a major role in the fighting with tumor, and the CIK or LAK cells' immunotherapy can play an antitumor role by restoring the patient's cellular immune responses; thus, the AIT treatment may hold a great promise in postoperative HCC.
An early study showed that both the recurrence and mortality were significantly decreased in AIT group compared with control group, and one included study reported that there were no died and no recurrence of patients in the 5-year follow-up. Moreover, another studies showed that the patients received immunotherapy had undergone fewer burden of micrometastases than those controls. Hence, the immunotherapy could improve the clinical outcome for postoperative HCC.
The protective role of postoperative immunotherapy in HCC patients appears to be enhanced by the adjuvant TACE and interferon (IFN).,, There was a significant reduction both recurrence and mortality in the studies that adjuvant TACE or IFN was used combined with postoperative immunotherapy compared than the studies only used the immunotherapy.,,, This phenomenon may be evaluated with the enhancement of immunity system. Various cytokines including IFN (IFN-α, IFN-β, and IFN-γ) were dysregulated in HCC progression and contribute to HCC progression, and the IFN may play an anticancer effect in HCC by inducing tumor cell apoptosis.,,,
There was no other severe side effect reported except the persistent fever due to the immunotherapy. On the contrary, several symptoms (appetite, sleep, and body weight) were ameliorated in HCC patients receiving the CIK treatment strategy. Therefore, immunotherapy not only improves the clinical prognosis but also improves the quality of life of postoperative HCC patients. Mo et al. investigated the role of AIT for HCC patients and demonstrated that adjuvant AIT for HCC patients after curative therapy reduces the risk of mortality rate and HCC recurrence, which is consistent with the findings of Yuan et al. Previous studies ,,,, have investigated the clinical efficacy of CIK cell infusions combined with alternative conventional therapies upon HCC patients and found that for HCC patients with Barcelona clinic liver cancer score ≤ B, CIK cell infusions combined with alternative conventional therapies significantly increased the recurrence-free survival and overall survival of HCC patients, suggesting that application of this AIT is highly recommended for the treatment of HCC.
However, there are several limitations in this systematic review. First, all eight included trials were from in Asia. Second, the number of patients involved in the study is not very large and the follow-up period was not very long in several articles. Third, the important features of HCC such as tumor size and HBV or HCV infection are not balanced. Fourth, not all the articles described the clinic random allocation concealment. All of those limitations weaken the strength of this study.
| > Conclusions|| |
This systematic review provides a strongly evidence on the safety and efficacy of AIT treatment for postoperative HCC patients and a striking difference between the two main treatment strategies (CIK and LAK). Based on the encouraging evidence, the AIT treatment has showed the power to improve the early clinical outcome (recurrence and survival rate) but has fails to ameliorate the late clinical outcome. Therefore, more studies are needed to investigate the effect of AIT treatment, to improve overall clinical outcome.
This research was supported by grants from the National Natural Science Foundation of China (No. 81660407).
Financial support and sponsorship
This research was supported by grants from the National Natural Science Foundation of China (No. 81660407) and The basic Research on the Application of Yunnan Province (No.2017FE468(-056).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]