Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: a systematic review and network meta-analysis

Abstract

Background: The trade-off between comparative effectiveness and reproductive morbidity of different treatment methods for cervical intraepithelial neoplasia (CIN) remains unclear. We aimed to determine the risks of treatment failure and preterm birth associated with various treatment techniques.

Methods: In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials database for randomised and non-randomised studies reporting on oncological or reproductive outcomes after CIN treatments from database inception until March 9, 2022, without language restrictions. We included studies of women with CIN, glandular intraepithelial neoplasia, or stage IA1 cervical cancer treated with excision (cold knife conisation [CKC], laser conisation, and large loop excision of the transformation zone [LLETZ]) or ablation (radical diathermy, laser ablation, cold coagulation, and cryotherapy). We excluded women treated with hysterectomy. The primary outcomes were any treatment failure (defined as any abnormal histology or cytology) and preterm birth (<37 weeks of gestation). The network for preterm birth also included women with untreated CIN (untreated colposcopy group). The main reference group was LLETZ for treatment failure and the untreated colposcopy group for preterm birth. For randomised controlled trials, we extracted group-level summary data, and for observational studies, we extracted relative treatment effect estimates adjusted for potential confounders, when available, and we did random-effects network meta-analyses to obtain odds ratios (ORs) with 95% CIs. We assessed within-study and across-study risk of bias using Cochrane tools. This systematic review is registered with PROSPERO, CRD42018115495 and CRD42018115508.

Findings: 7880 potential citations were identified for the outcome of treatment failure and 4107 for the outcome of preterm birth. After screening and removal of duplicates, the network for treatment failure included 19 240 participants across 71 studies (25 randomised) and the network for preterm birth included 68 817 participants across 29 studies (two randomised). Compared with LLETZ, risk of treatment failure was reduced for other excisional methods (laser conisation: OR 0·59 [95% CI 0·44-0·79] and CKC: 0·63 [0·50-0·81]) and increased for laser ablation (1·69 [1·27-2·24]) and cryotherapy (1·84 [1·33-2·56]). No differences were found for the comparison of cold coagulation versus LLETZ (1·09 [0·68-1·74]) but direct data were based on two small studies only. Compared with the untreated colposcopy group, risk of preterm birth was increased for all excisional techniques (CKC: 2·27 [1·70-3·02]; laser conisation: 1·77 [1·29-2·43]; and LLETZ: 1·37 [1·16-1·62]), whereas no differences were found for ablative methods (laser ablation: 1·05 [0·78-1·41]; cryotherapy: 1·01 [0·35-2·92]; and cold coagulation: 0·67 [0·02-29·15]). The evidence was based mostly on observational studies with their inherent risks of bias, and the credibility of many comparisons was low.

Interpretation: More radical excisional techniques reduce the risk of treatment failure but increase the risk of subsequent preterm birth. Although there is uncertainty, ablative treatments probably do not increase risk of preterm birth, but are associated with higher failure rates than excisional techniques. Although we found LLETZ to have balanced effectiveness and reproductive morbidity, treatment choice should rely on a woman's age, size and location of lesion, and future family planning.

Funding: National Institute for Health and Care Research: Research for Patient Benefit.

Figure 1

Study selection for oncological outcomes (A) and reproductive outcomes (B) after CIN treatments Where exclusion reasons include “or were unclear”, studies did not have sufficient information on the defined criterion to allow inclusion. CIN=cervical intraepithelial neoplasia. HPV=human papillomavirus. *More information is in the appendix (p 198).

Figure 2

Network plots for risk of CIN treatment failure (A) and preterm birth (B) The width of each line connecting two treatments is proportional to the inverse standard error of the fixed-effect summary effect size for these two treatments (number of studies for each pairwise meta-analysis is also shown). The diameter of each node is proportional to the number of women included in this group. As shown in part A, the network for treatment failure included a total of 19 240 women across 71 studies: CKC (34 studies; n=3865); laser conisation (19 studies; n=2473); LLETZ (43 studies; n=5644); radical diathermy (four studies; n=277); laser ablation (26 studies; n=3539); cold coagulation (six studies; n=667); and cryotherapy (18 studies; n=2775). As shown in part B, the network for preterm birth included a total of 68 817 women across 29 studies: CKC (14 studies; n=2598); laser conisation (nine studies; n=3799); LLETZ (25 studies; n=19 593); radical diathermy (one study; n=760); laser ablation (seven studies; n=1586); cold coagulation (one study; n=56); cryotherapy (three studies; n=67); and COLPO (ten studies; n=40 358). CIN=cervical intraepithelial neoplasia. CKC=cold knife conisation. COLPO=untreated colposcopy group. LLETZ=large loop excision of the transformation zone.

Figure 3

Unadjusted network meta-analyses for risk of CIN treatment failure and preterm birth, with LLETZ or COLPO as reference Data are odds ratios with 95% CIs indicated by error bars or in parentheses. In the network meta-analysis for preterm birth, 95% CIs for cold coagulation are not drawn due to very large uncertainty. CIN=cervical intraepithelial neoplasia. CKC=cold knife conisation. COLPO=untreated colposcopy group. LLETZ=large loop excision of the transformation zone. NA=not applicable.

Figure 4

League table of unadjusted network meta-analyses for risk of CIN treatment failure and preterm birth Data are odds ratio (95% CI; 95% prediction interval). The upper half of the grid shows odds ratios for treatment failure; the lower half of the grid shows odds ratios for preterm birth. Each box represents the comparison of the row-defining treatment versus the column-defining treatment. Odds ratios of more than 1 favour the column-defining treatment and odds ratios of less than 1 favour the row-defining treatment. The comparison of the column-defining treatment versus the row-defining treatment is the reciprocal of the data shown. CIN=cervical intraepithelial neoplasia. CKC=cold knife conisation. COLPO=untreated colposcopy group. LLETZ=large loop excision of the transformation zone. NA=not applicable

Figure 5

Absolute risks of CIN treatment failure and preterm birth (Kilim plot) Each box shows the absolute risk of treatment failure or preterm birth for each treatment. The colour correlates to the strength of the statistical evidence regarding the comparison of each treatment versus LLETZ. Colours correlating with a p value close to 1·00 indicate that there is paucity of evidence regarding whether the treatment is worse or better than LLETZ. LLETZ (the comparator) is shown in blue. CIN=cervical intraepithelial neoplasia. CKC=cold knife conisation. LLETZ=large loop excision of the transformation zone.