The clinical efficacy and safety of kanglaite adjuvant therapy in the treatment of advanced hepatocellular carcinoma: A PRISMA-compliant meta-analysis

Abstract Kanglaite, a type of Chinese medicine preparation, is considered a promising complementary therapy option for advanced hepatocellular carcinoma (HCC). Although an analysis of the published literature has been performed, the exact effects and safety are yet to be systematically investigated. Therefore, we conducted a wide-ranging online search of electronic databases to provide systematic conclusions; data from 31 trials with 2315 HCC patients were included. The results indicated that compared with conventional treatment (CT) alone, the combination of kanglaite with CT markedly prolonged patients’ 6-month overall survival (OS, P=0.003), 12-month OS (P<0.0001), 18-month OS (P=0.003), 24-month OS (P=0.03) and 36-month OS (P=0.0006) and significantly improved the overall response rate (odds ratio (OR) = 2.57, 95% confidence interval (CI) = 2.10–3.16, P<0.00001) and disease control rate (OR = 3.10, 95% CI = 2.42–3.97, P<0.00001) of patients. The quality of life (QoL), clinical symptoms and immune function of patients were also obviously improved after combined treatment. The incidence rates of nausea and vomiting (P=0.04), hepatotoxicity (P=0.0002), leukopenia (P<0.00001), thrombocytopenia (P<0.0001), gastrointestinal side effects (P=0.01) and fever (P<0.0009) were lower in the group receiving CT and kanglaite than in the group receiving CT alone. In summary, the combination of kanglaite and CT is safe and more effective in treating HCC than is CT alone, and its application in the clinic is worth promoting.

#5. limit #4 to (controlled clinical trial) #6. limit #5 to yr="2000.1-2019.5" 3. Prospective collection of data: data were collected according to a protocol established before the beginning of the study.

Supplementary
4. Endpoints appropriate to the aim of the study: unambiguous explanation of the criteria used to evaluate the main outcome which should be in accordance with the question addressed by the study. Also, the endpoints should be assessed on an intention-to-treat basis.
5. Unbiased assessment of the study endpoint: blind evaluation of objective endpoints and double-blind evaluation of subjective endpoints. Otherwise the reasons for not blinding should be stated.
6. Follow-up period appropriate to the aim of the study: the follow-up should be sufficiently long to allow the assessment of the main endpoint and possible adverse events.
7. Loss to follow up less than 5%: all patients should be included in the follow up. Otherwise, the proportion lost to follow up should not exceed the proportion experiencing the major endpoint.
8. Prospective calculation of the study size: information of the size of detectable difference of interest with a calculation of 95% confidence interval, according to the expected incidence of the outcome event, and information about the level for statistical significance and estimates of power when comparing the outcomes.

Additional criteria in the case of comparative study
9. An adequate control group: having a gold standard diagnostic test or therapeutic intervention recognized as the optimal intervention according to the available published data.
10. Contemporary groups: control and studied group should be managed during the same time period (no historical comparison).
11. Baseline equivalence of groups: the groups should be similar regarding the criteria other than the studied endpoints. Absence of confounding factors that could bias the interpretation of the results.

Adequate statistical analyses:
whether the statistics were in accordance with the type of study with calculation of confidence intervals or relative risk.
*The items are scored 0 (not reported), 1 (reported but inadequate) or 2 (reported and adequate). Study selection 5-6 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

Supplementary
Page 5-6 (Data extraction and quality assessment, Supplementary Table 2) Data collection process 5-6 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
Page 5-6 (Data extraction and quality assessment, Supplementary Table 2) Data items 6 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Risk of bias in individual studies
5-6 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
Page 5-6 (Data extraction and quality assessment, Supplementary Table 2) Summary measures 6 State the principal summary measures (e.g., risk ratio, difference in means). Page 6 (Outcome definition) Synthesis of results 6-7 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis.

Section/topic # Checklist item Reported on page #
Risk of bias across studies 6-7 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

RESULTS
Study selection 7 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
Page 7 (Search results, Fig 2) Study characteristics 7-8 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.  4-9, Supplementary  Fig 1 and 2) Risk of bias across studies 10-11 Present results of any assessment of risk of bias across studies (see Item 15). Page 10-11 (Publication bias, Fig 10) Additional analysis 12 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).

DISCUSSION
Summary of evidence 11-14 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
Page 11-14 (Discussion) Limitations 13-14 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). For more information, visit: www.prisma-statement.org.