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Appendices
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor: [Uterine Cervical Neoplasms] this term only
# 2 MeSH descriptor: [Uterine Cervical Dysplasia] this term only
#3 MeSH descriptor: [Cervical Intraepithelial Neoplasia] this term only
#4 (cervi* near/5 (neoplas* or tumor* or tumour* or malignan* or carcinoma* or cancer* or dysplas* or intraepithel* or intra‐epithel*))
#5 #1 or #2 or #3 or #4
#6 MeSH descriptor: [Anti‐Inflammatory Agents] explode all trees
#7 (anti‐inflammatory or antiinflammatory)
#8 NSAID*
#9 (cyclo‐oxygenase or cyclooxygenase)
#10 #6 or #7 or #8 or #9
#11 #5 and #10
Appendix 2. MEDLINE search strategy
1 Uterine Cervical Neoplasms/
2 Uterine Cervical Dysplasia/
3 Cervical Intraepithelial Neoplasia/
4 (cervi* adj5 (neoplas* or tumour* or tumour* or malignan* or carcinoma* or cancer* or dysplas* or intraepithel* or intra‐epithel*)).mp.
5 1 or 2 or 3 or 4
6 exp Anti‐Inflammatory Agents/
7 (anti‐inflammatory or antiinflammatory).mp.
8 NSAID*.mp.
9 (cyclo‐oxygenase or cyclooxygenase).mp.
10 6 or 7 or 8 or 9
11 5 and 10
12 randomised controlled trial.pt.
13 controlled clinical trial.pt.
14 randomized.ab.
15 placebo.ab.
16 drug therapy.fs.
17 randomly.ab.
18 trial.ab.
19 groups.ab.
20 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19
21 11 and 20
22 exp animals/ not humans.sh.
23 21 not 22
key:
mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier
pt=publication type
ab=abstract
sh=subject heading
ti=title
Appendix 3. Embase search strategy
1 exp uterine cervix tumour/
2 uterine cervix dysplasia/
3 uterine cervix carcinoma in situ/
4 (cervi* adj5 (neoplas* or tumour* or tumour* or malignan* or carcinoma* or cancer* or dysplas* or intraepithel* or intra‐epithel*)).mp.
5 1 or 2 or 3 or 4
6 exp antiinflammatory agent/
7 (anti‐inflammatory or antiinflammatory).mp.
8 NSAID*.mp.
9 (cyclo‐oxygenase or cyclooxygenase).mp.
10 6 or 7 or 8 or 9
11 5 and 10
12 exp controlled clinical trial/
13 crossover procedure/
14 double‐blind procedure/
15 randomised controlled trial/
16 single‐blind procedure/
17 random*.mp.
18 factorial*.mp.
19 (crossover* or cross over* or cross‐over*).mp.
20 placebo*.mp.
21 (double* adj blind*).mp.
22 (singl* adj blind*).mp.
23 assign*.mp.
24 allocat*.mp.
25 volunteer*.mp.
26 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25
27 11 and 26
28 (exp animal/ or nonhuman/ or exp animal experiment/) not human/
29 27 not 28
key:
mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword
Appendix 4. Risk of bias tool
We applied this tool to included studies to assess the risk of bias.
1. Random sequence generation
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Low risk of bias e.g. participants assigned to treatments on basis of a computer‐generated random sequence or a table of random numbers.
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High risk of bias e.g. participants assigned to treatments on basis of date of birth, clinic ID number or surname, or no attempt to randomise participants.
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Unclear risk of bias e.g. not reported, information not available.
2. Allocation concealment
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Low risk of bias e.g. where the allocation sequence could not be foretold.
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High risk of bias e.g. allocation sequence could be foretold by patients, investigators or treatment providers.
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Unclear risk of bias e.g. not reported.
3. Blinding of participants and personnel
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Low risk of bias if participants and personnel were adequately blinded.
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High risk of bias if participants were not blinded to the intervention that the participant received.
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Unclear risk of bias if this was not reported or unclear.
4. Blinding of outcomes assessors
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Low risk of bias if outcome assessors were adequately blinded.
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High risk of bias if outcome assessors were not blinded to the intervention that the participant received.
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Unclear risk of bias if this was not reported or unclear.
5. Incomplete outcome data
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Low risk of bias, if fewer than 20% of patients were lost to follow‐up and reasons for loss to follow‐up were similar in both treatment arms.
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High risk of bias, if more than 20% of patients were lost to follow‐up or reasons for loss to follow‐up differed between treatment arms.
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Unclear risk of bias, if loss to follow‐up was not reported.
6. Selective reporting of outcomes
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Low risk of bias e.g. reports all outcomes specified in the protocol.
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High risk of bias e.g. it is suspected that outcomes have been selectively reported.
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Unclear risk of bias e.g. if it is unclear whether outcomes have been selectively reported.
7. Other bias
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Low risk of bias if you do not suspect any other source of bias and the trial appears to be methodologically sound.
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High risk of bias if you suspect that the trial was prone to an additional bias.
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Unclear risk of bias if it is uncertain whether an additional bias may have been present.
Study flow diagram.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Progression of CIN, Outcome 1 Progression of CIN to higher grade of CIN.
Comparison 2 Regression of CIN 2 and 3, Outcome 1 Partial or complete regression of CIN 2 or CIN 3.
Comparison 2 Regression of CIN 2 and 3, Outcome 2 Complete regression of CIN 2 or CIN 3.
Comparison 2 Regression of CIN 2 and 3, Outcome 3 Partial regression of CIN 2 or CIN 3.
| Non‐steroidal anti‐inflammatory agents (NSAIDs) compared with placebo for CIN 2 or CIN 3 | ||||||
| Patient or population: women with CIN 2 or CIN 3 Settings: outpatient Intervention: celecoxib 400 mg by mouth daily for 14‐18 weeks, celecoxib 200 mg by mouth twice daily for six months or rofecoxib 40 mg by mouth daily for three months Comparison: placebo tablet by mouth, daily for three to six months | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of Participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Progression of CIN to a higher grade of CIN | 77 per 10001 | 42 per 1000 | RR 0.54 (0.06 to 5.24) | 25 (one study) | ⊕⊝⊝⊝3 | |
| Partial or complete regression of CIN 2 or CIN 3 | 308 per 10002 | 447 per 1000 | RR 1.45 (0.93 to 2.27) | 132 (three studies) | ⊕⊕⊕⊝3 | |
| Complete regression of CIN 2 or CIN 3 | 174 per 10001 | 228 per 1000 | RR 1.31 (0.65 to 2.67) | 116 (two studies) | ⊕⊕⊕⊝3 | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1The basis for the assumed risk is from the spontaneous complete regression rate in the placebo arm of Farley 2006 and Rader 2017 2 The basis for the assumed risk is from the combined spontaneous partial or complete regression rates in the placebo arms of Farley 2006; Hefler 2006; Rader 2017 3Given the increased sample size with the addition of Rader 2017, we have upgraded the certainty to high other than the Progression analysis as it is based on one small study and thus remained very low certainty. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Progression of CIN to higher grade of CIN Show forest plot | 1 | 25 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.54 [0.06, 5.24] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Partial or complete regression of CIN 2 or CIN 3 Show forest plot | 3 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.45 [0.93, 2.27] |
| 2 Complete regression of CIN 2 or CIN 3 Show forest plot | 2 | 116 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.31 [0.65, 2.67] |
| 3 Partial regression of CIN 2 or CIN 3 Show forest plot | 2 | 116 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.56 [0.72, 3.40] |
