JOURNAL CLUB PRESENTATION

TITLE:Impact of combined immune checkpoint inhibitors in the

treatment of non-small cell lung cancer: A meta analysis of
clinical trials
Journal Name: Journal of Clinical Oncology(2022)

Presented by: Christo Sebastian

5th Pharm D
Reg. no. 18Q0304
TITLE
1. Identify the report as a systematic review, meta-analysis, or both.

Its Identified as a systematic review and meta-analysis in the title[Page:5]

ABSTRACT
2. Provide a structured summary including, as applicable: background; objectives; data sources; study
eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations;
conclusions and implications of key findings; systematic review registration number.

1. Background and Objectives[Page:5]

Anti-seizure medications (ASMs) have been used historically as treatment options in alcohol withdrawal syndrome
(AWS). In the past 10 years, there have been no large-scale meta-analyses comparing ASMs with placebo or the
current AWS treatment standard, benzodiazepines. We aimed to evaluate the efficacy and tolerability of ASMs in AWS.
2. Data sources[Page:5]
Medline, Embase and Psych INFO
3. Study eligibility criteria[Page:6]
Participants were diagnosed with AWS using the standardized criteria that were in general use at the time of the study
(i.e. DSM III-IV or ICD-10) and where participants were adults age >18 years, irrespective of gender, nationality and
inpatient or outpatient therapy.
ABSTRACT
4. Participants[Page:5]
adults age >18 years with AWS
5. Intervention[Page:6]
Group 1: Participants that were given ASMs
Group 2: Participants that were given a combination of ASMs and BDZ

6. Study appraisal and synthesis methods[Page:5]

Quality was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE).
ABSTRACT
7. Results[Page:5]
There was no evidence of significant improvements in any efficacy outcomes when comparing ASMs with placebo or
benzodiazepines. When compared with benzodiazepines, ASMs demonstrated significantly increased odds of requiring
rescue medications (OR = 3.50, 95% CI = 1.32, 9.28; P = 0.012).
8. Limitations[Page:5]
When comparing ASMs with placebo, there were significantly more dropouts because of adverse events (OR = 1.86,
95% CI = 1.05, 3.28; P = 0.034). Most results were of very low quality with the majority of included studies conducted
before 2000.
9. Conclusions[Page:5]
This systematic review and meta-analysis found no evidence to support general first line clinical use of anti-seizure
medications in alcohol withdrawal syndrome treatment.
10. Key findings[Page:5]
Alcohol withdrawal, anticonvulsants, anti-epileptic drugs, anti-seizure medications, GRADE, meta-analysis.
11. Systematic review registration number
No Registration number found
INTRODUCTION- RATIONALE
3. Describe the rationale for the review in the context of what is already known.[Page:5,6]

There has been evidence suggesting some ASMs (e.g. topiramate) may be helpful in reducing craving for alcohol,
therefore if certain ASMs were effective and tolerable in both the treatment of AWS and in relapse prevention the same
pharmacotherapy could be continued without a need to switch medications following AWS treatment, as is current
common practice. This has the potential to lead to improved medication adherence and better treatment outcomes.

OBJECTIVES
4. Provide an explicit statement of questions being addressed with reference to participants, intervention,
comparison, outcomes, and study design(PICOS)[Page:6]

We aimed to conduct a systematic review and meta-analysis, the objectives of which were: (i) to evaluate the
effectiveness of ASMs in AWS treatment; (ii) to evaluate the tolerability of ASMs in AWS treatment; and (iii) to use
GRADE methodology to assess the quality of evidence and the strength of any resultant recommendations.
INFORMATION SOURCES
7. Describe all information sources(e.g., databases with dates of coverage, contact with study authors to identify
additional studies) in the search and date last searched.[Page:6]

We searched Medline, Embase and Psych INFO from 1 January 2009 to 14 March 2020, without language restriction.
This period was chosen to include the latest studies after the most recent large-scale Cochrane systematic review and
meta-analysis by Minozzi et al., which included papers concerning use of ASMs in AWS until December 2009.

SEARCH
8. Present full electronic search strategy for at least one database, including any limits used, such that it could be
repeated. [Page:6]

Medline, Embase and Psych INFO

STUDY SELECTION
9. State the process for selecting studies(i.e., screening, eligibility, included in systematic review, and, if applicable,
included in the meta analysis).[Page:6]

Two authors (J.Y.L. and E.R.) initially assessed titles and abstracts and reviewed the full text of the remaining articles for
inclusion. Any discrepancy was resolved by discussion, and where agreement could not be reached a third author (N.K.)
was consulted. All relevant references were checked for additional citations. We included studies where randomized
controlled trials (RCTs) evaluated the effectiveness or tolerability of ASMs for the treatment of AWS. Included studies
were those in which participants were diagnosed with AWS using the standardized criteria that were in general use at the
time of the study (i.e. DSM III-IV or ICD-10) and where participants were adults age >18 years, irrespective of gender,
nationality and inpatient or outpatient therapy.

DATA COLLECTION PROCESS

10. Describe method of data extraction from reports(e.g., piloted forms, independently, in duplicate) and any
process for obtaining and confirming data from investigators.[Page:7]

Two authors (J.Y.L. and E.R.) independently extracted data from all eligible studies using a standardized data extraction
spreadsheet. In the case of incomplete reporting of data, we searched studies online supplementary appendices and
contacted authors as necessary. Any discrepancy was resolved by discussion and where agreement could not be reached a
third author (N.K.) was consulted.
DATA ITEMS
11. List and define all variables for which data were sought(e.g., PICOS, funding sources) and any assumptions
and simplifications made.[Page:7]

Binary outcomes were analyzed by calculating the OR with 95% CI, and continuous outcomes were analyzed by
calculating the standardized mean difference (SMD) with 95% CI. Heterogeneity in primary outcome studies was
assessed using the I2 statistic, GRADE quality score was downgraded by one level if the I2 was >50% but ≤75% and by
two levels if the I2 was >75%. All analyses were conducted in STATA IC version 15, with the significance level set at
0.05. This study was supported and funded by King's College London.

RISK OF BIAS IN INDIVIDUAL STUDIES

12. 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:7]

Risk of bias was assessed using the Cochrane risk of bias assessment tool
SUMMARY MEASURES
13. State the principal summary measures (e.g., risk ratio, differences in means)[Page:7]

Binary outcomes were analyzed by calculating the OR with 95% CI, and continuous outcomes were analysed by
calculating the standardized mean difference (SMD) with 95% CI. Heterogeneity in primary outcome studies was
assessed using the I2 statistic, GRADE quality score was downgraded by one level if the I2 was >50% but ≤75% and by
two levels if the I2 was >75%. All analyses were conducted in STATA IC version 15, with the significance level set at
0.05.

SYNTHESIS OF RESULTS
14. Describe the methods of handling data and combining results of studies, if done, including measures of
consistency( e.g., I2 )[Page:7]

Heterogeneity in primary outcome studies was assessed using the I2 statistic, GRADE quality score was downgraded by
one level if the I2 was >50% but ≤75% and by two levels if the I2 was >75%.
RISK OF BIAS ACROSS STUDIES
15. Specify any assessment of risk of bias that may affect the cumulative evidence (e,g., publiaction bias, selective
reporting within studies).[Page:8,17]

We performed random-effects meta-analysis, and funnel plots were generated for each outcome with Egger's test used to
assess the potential for publication bias which was not found. Most outcomes of this meta-analysis were rated as ‘very
low’ in quality according to GRADE system, the downgrading caused mainly by high risk of bias scores because of lack
of methodological reporting. There were substantially high dropout rates in most RCTs, leading to high risk of bias
judgments regarding attrition bias.

ADDITIONAL ANALYSIS
16. Describe methods of additional analyses (e.g., sensitivity or subgroups analyses, meta regression), if done,
indicating which were pre specified.

Not found in this study

RESULTS- STUDY SELECTION
17. 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:8]
STUDY CHARACTERISTICS
18. For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow up period)
and provide the citations.[Page:6]

Previously shown in question 4

RISK OF BIAS WITHIN STUDIES

19. Present data on risk of bias of each study and, if available, any outcome level assessment( see item 12)[Page:7]

Risk of bias was assessed using the Cochrane risk of bias assessment tool .The main outcome for ASM tolerability was the
number of people who dropped out because of adverse events (AEs).
RESULTS OF INDIVIDUAL STUDIES
20. For all outcomes considered (benefits of harm), present for each study.[Page:13-16]
a. simple summary data for each intervention group.
b. effect estimates and confidence intervals, ideally with a forest plot
SYNTHESIS OF RESULTS
21. Present results of each meta analyses done, including confidence intervals and measures of consistency.
[Page:8,12]
With regards effectiveness outcomes, there was insufficient evidence to support general first line clinical use of ASMs in
AWS treatment. There were statistically significant results that benzodiazepines worked better than ASMs in reducing
rescue medication requirements in AWS. Although there was evidence of reduced odds of requiring rescue medications
when treating AWS with ASMs compared to placebo, when compared to benzodiazepines, there was an overall increased
odds of requiring rescue medication (OR = 3.50, 95% CI = 1.32, 9.28; P = 0.012; I2 = 0.0%). When examining individual
ASMs versus benzodiazepines topiramate performed worse than diazepam, whereas lamotrigine and zonisamide were no
different when compared to diazepam. All results were of low or very low quality according to GRADE.

With regards tolerability outcomes when ASMs were compared to placebo, five RCTs with 368 participants showed
increased odds of people dropping out because of adverse events with ASMs (OR = 1.86, 95% CI = 1.05, 3.28; P = 0.034;
I2 = 65.2%; Fig. 4). This effect was largely driven by the contribution of two RCTs comparing carbamazepine versus
placebo. There were no evidence of significant differences between ASMs versus benzodiazepines, or ASMs combined
with benzodiazepines versus benzodiazepines. All estimates were of very low quality according to GRADE
RISK OF BIAS ACROSS STUDIES
22. Present results of any assessment of risk of bias across studies( see item 15)[Page:16]
Most outcomes of this meta-analysis were rated as ‘very low’ in quality according to GRADE system, the downgrading
caused mainly by high risk of bias scores because of lack of methodological reporting. There were substantially high dropout
rates in most RCTs, leading to high risk of bias judgments regarding attrition bias. This is another major difference from
previous studies, because no previous reviews have used GRADE methodology, we can report that any newly conducted
trials are likely to affect almost all estimates.

ADDITIONAL ANALYSIS
23. Give results of additional analyses, if done( e.g., sensitivity or subgroup analyses, meta regression) (see item 16)

Not found in this study

DISCUSSION- SUMMARY OF EVIDENCE
24. 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:12,14]

There was insufficient evidence to support general first line clinical use of ASMs in AWS treatment. Because of the small
number of participants, results were both merged to see the tendency of comparison results by class and examined
individually. There is no evidence that ASMs should replace benzodiazepines as a first line AWS treatment. As assessed by
GRADE, most estimates were of very low quality, largely because of risk of bias as the majority of RCTs were conducted
before 2000 with limited methodological reporting.
LIMITATIONS
25. 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).[Page:14]

This systematic review and meta-analysis has some major limitations.

-limited RCT data is available for newer ASMs.
-they were published in an era where there were fewer reporting standards.
-AEs were not reported clearly in the majority of studies
-unclear how patients with more complex physical health conditions would respond to ASMs as an AWS treatment.
-few patients may have been at genuine risk of developing alcohol withdrawal seizures particularly given that many
studies had high dropout rates, between 10% and 30%, but note that high dropout have contributed to reduced quality of
the generated estimates.
CONCLUSION
26. Provide a general interpretation of the results in the context of other evidence, and implications of future
research. [Page:16]
There was insufficient evidence to support general first line clinical use of ASMs in AWS treatment. Although ASMs
seemed to have limited side effects, there was limited evidence of their effectiveness compared to placebo. Included RCTs
were largely conducted on small numbers of participants and the results of most outcomes did not reach statistical
significance. This is the most up to date review, and the first to use GRADE to evaluate the strength of evidence. Further
studies on the effectiveness and tolerability of ASMs should consider recruiting people with more severe AWS and should
prioritise studies of zonisamide, lamotrigine and levetiracetam.
THANK
YOU