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Tang et al. Hepatoma Res 2019;5:19 I http://dx.doi.org/10.20517/2394-5079.2019.07 Page 7 of 9

Table 2. The rate of major adverse events and their 95% confidence interval
Adverse Events Event rate on all grade (95%CI) Ref. Event rate on grade > 3 (95%CI) Ref.
Fatigue 20.8% (10.9%-36.3%) [15,17-21] 1.9% (0.9%-3.9%) [15,17-21]
Pruritus 17.3% (13.5%-21.8%) [16-21] 1.3% (0.4%-3.6%) [16-21]
Rash 18.5% (8.9%-34.4%) [15-20] 1.6% (0.5%-5.1%) [15-20]
Diarrhoea 12.5% (7.9%-19.1%) [15,17-20] 1.5% (0.3%-6.6%) [15,17-20]
Nausea 7.3% (5.0%-10.6%) [15,17-19] 1.8% (0.4%-8.3%) [15,17-19]
Asthenia 6.2% (4.1%-9.1%) [17-20] 0.9% (0.2%-3.4%) [17-20]
Pulmonary toxicity* 3.3% (1.5%-6.8%) [15-17,19-21] 1.9% (0. 7%-5.1%) [15-17,19-21]
Increased AST 22.7% (13.8%-35.2%) [16-21] 9.9% (4.4%-21.0%) [16-21]
Increased ALT 13.9% (8.8%-21.3%) [16-20] 5.8% (3.7%-8.9%) [16-20]

and clinical trials with other endpoints (such as overall survival, OS).

ICIs targeting CTLA-4 and PD-1/PDL-1 have dramatically changed the outcomes of patients with advanced-
stage malignancies. However, ICIs may cause unique side effects, known as immune-related adverse events
(irAEs). These side effects are mostly transient and mild, but can occasionally be fatal. Our analysis indicated
that the most common AEs associated with ICIs treatment in HCC patients was increased AST (22.73%, 95%CI:
13.8%-35.2%), which was also the most common AEs of grade greater than 3 (9.94%, 95%CI: 4.4%-21.0%). This
result is inconsistent with previous studies on other cancers. Respectively, the most common AEs and severe
AEs (grade 3-4) were fatigue in NSCLC [26,27] , fatigue and lipase elevation or fatigue and rash in melanoma [28,29] ,
[31]
[30]
low appetite and asthenia in urothelial carcinoma , rash and lipase elevation in Hodgkin’s lymphoma , and
[32]
neutropenia in lymphoma . Patients with HCC treated with ICIs presented adverse event of fatigue in the
second common place followed by rash and fatigue. Rash and fatigue are high incidence skin AEs. Skin AEs are
[33]
the most original irAE, taking place every 3.6 weeks after treatment . The pooled estimated incident rate of
diarrhea is 12.46% (95%CI: 7.9%-19.1%), which was the most common reported gastrointestinal toxicity. Other
gastrointestinal toxicities such as abdominal pain, constipation, vomiting, were rarely reported and not taken
into consideration here. Result from recent research showed that the incidence rate of diarrhea was higher with
[34]
CTLA-4 blocked than the PD-1/PD-L1 blocked . Adverse events of instance nausea, asthenia and pulmonary
toxicity were less commonly reported in this study.

There are still some limitations in this study. Firstly, the final 7 studies included were all non-randomized
controlled clinical trials; it might produce bias and downgrade the level of evidence. Secondly, some
factors such as the origin of the HCC and patients' race might produce bias on outcomes, which can not be
controlled in this meta analysis. However, the ORR is a straightforward index in evaluating the effectiveness
of immunotherapy, and result from this meta analysis can be referred in clinical application.

DECLARATIONS
Authors’ contributions
Conception and design: Zhang HW, Tang WN
Date analysis and interpretation: Tang WN, Ma LT, Deng Y, Wang W
Manucript preparation: Tang WN, Wang W
Critical revision and finalizing of the manuscript: Zhang HW

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by National Key Basic Research Program of China (No. 2015CB554000).

Conflicts of interest
All authors declared that there are no conflicts of interest.