Kapp Philipp, Schmucker Christine, Siemens Waldemar, Brugger Timo, Gorenflo Lea, Röbl-Mathieu Marianne, Grummich Kathrin, Thörel Eberhard, Askar Mona, Brotons Maria, Andersen Peter Henrik, Konopnicki Deborah, Lynch Judi, Ruta Simona, Saare Liisa, Swennen Beatrice, Tachezy Ruth, Takla Anja, Učakar Veronika, Vänskä Simopekka, Zavadska Dace, Adel Ali Karam, Olsson Kate, Harder Thomas, Meerpohl Joerg J
Institute for Evidence in Medicine, Medical Center - University of Freiburg / Medical Faculty - University of Freiburg, Freiburg, Germany.
Cochrane Germany, Cochrane Germany Foundation, Freiburg, Germany.
Cochrane Database Syst Rev. 2025 Sep 8;9(9):CD016121. doi: 10.1002/14651858.CD016121.
Cervical cancer is the fourth most common cancer affecting women worldwide, caused by persistent infection with oncogenic human papillomavirus (HPV) types. While HPV infections usually resolve spontaneously, persistent infections with high-risk HPV types can progress to premalignant glandular or - mostly - squamous intraepithelial lesions, usually classified in cervical intraepithelial neoplasia (CIN). Women with CIN 2 and CIN 3 (i.e. high-grade CIN) typically undergo cervical conisation to remove precancerous cervical lesions. While conisation is effective, there is a risk of recurrence and progression to invasive cervical cancer. Additionally, women who have undergone conisation are at higher risk of HPV-associated anogenital precancerous lesions and cancers in other locations. HPV vaccination is an important measure to prevent HPV-related cancer. It is unclear to what extent HPV vaccination offers protection to women with conisation. Of note, the term 'with conisation' is interchangeably used for all time points of HPV vaccination relative to the conisation procedure for the purpose of this review.
To investigate the benefits and harms of HPV vaccination (given shortly before, at, or after conisation) in comparison to no HPV vaccination in women with conisation.
We searched CENTRAL, MEDLINE, Embase, and Clarivate Web of Science (May 2023). We also searched ClinicalTrials.gov to identify ongoing studies.
We included randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSI) if they compared an HPV vaccine (nonavalent, quadrivalent, or bivalent) with no HPV vaccine, placebo, or other vaccines not directed against HPV in women of any age with conisation for treating precancerous lesions following HPV infection.
Critical outcomes: CIN 2+ (irrespective of HPV type and related to HPV 16/18), CIN 3+ (irrespective of HPV type and related to HPV 16/18), incident invasive cervical cancer (irrespective of HPV type and related to HPV 16/18), persistent HPV infection (irrespective of HPV type and related to HPV 16/18) and incident HPV infection (irrespective of HPV type and related to HPV 16/18).
We evaluated RCTs using the Cochrane RoB 2 tool and NRSI using the 'Risk of Bias in Non-randomised Studies of Interventions' tool (ROBINS-I).
Two review authors independently screened, extracted data, and assessed risk of bias. We used random-effects meta-analyses for our primary analyses. We rated the certainty of evidence using the GRADE approach.
The search identified 13 studies (2 RCTs, 11 NRSI), with 21,453 women with conisation. Studies were conducted in Europe (10), China (1), South Korea (1), and Iran (1), and published between 2013 and 2023. The length of follow-up after conisation was up to 36 months in RCTs and up to greater than 60 months in NRSI. Eight studies included women older than 25 years. The remaining studies included women across different age groups (range 17 to greater than 50 years). In 10 studies, the treatment for cervical lesions included loop electrosurgical excision procedures or large loop excision of the transformation zone as the conisation procedure. The spectrum of precancerous lesions (in terms of baseline characteristics) varied widely between women. Seven studies used the quadrivalent HPV vaccine, one used the nonavalent HPV vaccine, four used various HPV vaccine types, and one did not specify the HPV vaccine type. All studies compared the HPV vaccine with no intervention.
Critical outcomes HPV vaccination compared to no HPV vaccination in women with conisation may reduce the risk of CIN 2+ (evidence from RCTs: risk ratio (RR) 0.40, 95% confidence interval (CI) 0.26 to 0.63; 2 RCTs, 420 women; evidence from NRSI: hazard ratio (HR) 0.49, 95% CI 0.27 to 0.89; 5 NRSI, 19,059 women; odds ratio (OR) 0.23, 95% CI 0.05 to 0.97; 3 NRSI, 928 women; RR 0.24, 95% CI 0.13 to 0.46; 3 NRSI, 1027 women; low-certainty evidence). There were similar results for CIN 2+ (related to HPV 16/18) (evidence from NRSI: RR 0.38, 95% CI 0.21 to 0.68; 7 NRSI, 2970 women; low-certainty evidence). Effects on CIN 3+ varied between studies. One study suggested similar effects to CIN 2+ favouring HPV vaccination (evidence from NRSI: OR 0.20, 95% CI 0.10 to 0.60; 1 NRSI, 285 women; low-certainty evidence), while the remaining evidence was very uncertain (evidence from NRSI: RR 0.53, 95% CI 0.15 to 1.90; 2 NRSI, 17,472 women; very low-certainty evidence). The evidence on CIN 2+ (related to HPV 16/18) based on RCT evidence was very uncertain. The evidence on CIN 3+ (related to HPV 16/18), incident invasive cervical cancer (irrespective of HPV type), and persistent HPV infections (irrespective of HPV type and related to HPV 16/18) was very uncertain. Adverse events One RCT reported minor local reactions (redness and rash: 127/138 (92%) women; headache: 11/138 (8%) women) and severe allergies (2/158 (1%) women).
AUTHORS' CONCLUSIONS: HPV vaccination given around the time of conisation in comparison to no HPV vaccination in women with conisation may reduce the risk of CIN 2+ and CIN 2+ (related to HPV 16/18; evidence based on NRSI). Effects on CIN 3+ (irrespective of HPV type) varied, with one NRSI suggesting similar effects to CIN 2+, while the remaining evidence was very uncertain. The evidence on other outcomes was predominantly very uncertain or inconclusive. Overall, the existing evidence for HPV vaccination in women with conisation is largely based on NRSI with serious or critical risk of bias and low- to very low-certainty evidence. Evidence from RCTs is limited (i.e. only two RCTs are available). Additional RCTs with a placebo intervention in the control group to evaluate the efficacy and safety of HPV vaccination (particularly with the nonavalent vaccine) as an adjuvant to conisation would provide more robust evidence. Future RCTs should also aim to assess how effects of vaccination around the time of conisation vary according to whether a previous HPV vaccine for primary prevention was received, timing of HPV vaccination related to conisation, and different age groups.
EU4Health Programme.
PROSPERO (CRD42023428998).
宫颈癌是全球影响女性的第四大常见癌症，由致癌性人乳头瘤病毒（HPV）持续感染引起。虽然HPV感染通常会自行消退，但高危型HPV的持续感染可能会进展为癌前腺性病变或——大多数情况下——鳞状上皮内病变，通常归类为宫颈上皮内瘤变（CIN）。患有CIN 2和CIN 3（即高级别CIN）的女性通常会接受宫颈锥切术以切除宫颈癌前病变。虽然锥切术有效，但存在复发和进展为浸润性宫颈癌的风险。此外，接受过锥切术的女性患HPV相关肛门生殖器癌前病变和其他部位癌症的风险更高。HPV疫苗接种是预防HPV相关癌症的一项重要措施。目前尚不清楚HPV疫苗接种对接受锥切术的女性能提供多大程度的保护。需要注意的是，在本综述中，“接受锥切术”一词在HPV疫苗接种相对于锥切术的所有时间点均可互换使用。
研究与未接种HPV疫苗相比，HPV疫苗接种（在锥切术前、术中或术后不久接种）对接受锥切术的女性的益处和危害。
我们检索了CENTRAL、MEDLINE、Embase和科睿唯安Web of Science（2023年5月）。我们还检索了ClinicalTrials.gov以识别正在进行的研究。
如果随机对照试验（RCT）和非随机干预研究（NRSI）将HPV疫苗（九价、四价或二价）与未接种HPV疫苗、安慰剂或其他非针对HPV的疫苗进行比较，纳入任何年龄接受锥切术以治疗HPV感染后癌前病变的女性。
关键结局指标：CIN 2+（无论HPV类型，与HPV 16/18相关）、CIN 3+（无论HPV类型，与HPV 16/18相关）、新发浸润性宫颈癌（无论HPV类型，与HPV 16/18相关）、持续性HPV感染（无论HPV类型，与HPV 16/18相关）和新发HPV感染（无论HPV类型，与HPV 16/18相关）。
我们使用Cochrane偏倚风险评估工具2评估RCT，使用“非随机干预研究的偏倚风险”工具（ROBINS-I）评估NRSI。
两位综述作者独立筛选、提取数据并评估偏倚风险。我们在主要分析中使用随机效应荟萃分析。我们使用GRADE方法对证据的确定性进行评级。
检索共识别出13项研究（2项RCT，11项NRSI），涉及21453名接受锥切术的女性。研究在欧洲（10项）、中国（1项）、韩国（1项）和伊朗（1项）开展，发表时间为2013年至2023年。RCT中锥切术后的随访时间最长为36个月，NRSI中最长超过60个月。8项研究纳入了年龄大于25岁的女性。其余研究纳入了不同年龄组的女性（年龄范围17至大于50岁）。10项研究中，宫颈病变的治疗方法包括环形电切术或转化区大环形切除术作为锥切术。癌前病变的范围（就基线特征而言）在女性之间差异很大。7项研究使用了四价HPV疫苗，1项使用了九价HPV疫苗，4项使用了各种HPV疫苗类型，1项未指明HPV疫苗类型。所有研究均将HPV疫苗与未干预进行了比较。
关键结局指标与未接种HPV疫苗相比，HPV疫苗接种可能会降低接受锥切术女性发生CIN 2+的风险（RCT证据：风险比（RR）0.40，95%置信区间（CI）0.26至0.63；2项RCT，420名女性；NRSI证据：风险比（HR）0.49，95%CI 0.27至0.89；5项NRSI，19059名女性；比值比（OR）0.23，95%CI 0.05至0.97；3项NRSI, 928名女性；RR 0.24，95%CI 0.13至0.46；3项NRSI，1027名女性；低确定性证据）。CIN 2+（与HPV 16/18相关）也有类似结果（NRSI证据：RR 0.38，95%CI 0.21至0.68；7项NRSI，2970名女性；低确定性证据）。不同研究中对CIN 3+的影响各不相同。一项研究表明对CIN 3+的影响与CIN 2+相似，支持HPV疫苗接种（NRSI证据：OR 0.20，95%CI 0.10至0.60；1项NRSI，285名女性；低确定性证据），而其余证据非常不确定（NRSI证据：RR 0.53，95%CI 0.15至1.90；2项NRSI，17472名女性；极低确定性证据）。基于RCT证据的CIN 2+（与HPV 16/18相关）的证据非常不确定。关于CIN 3+（与HPV 16/18相关）、新发浸润性宫颈癌（无论HPV类型）和持续性HPV感染（无论HPV类型，与HPV 16/18相关）的证据非常不确定。不良事件一项RCT报告了轻微的局部反应（发红和皮疹：127/138（92%）女性；头痛：11/138（8%）女性）和严重过敏反应（2/158（1%）女性）。
与未接种HPV疫苗相比，在接受锥切术的女性中，在锥切术前后接种HPV疫苗可能会降低CIN 2+和CIN 2+（与HPV 16/18相关；基于NRSI证据）的风险。对CIN 3+（无论HPV类型）的影响各不相同，一项NRSI表明与CIN 2+的影响相似，而其余证据非常不确定。关于其他结局指标的证据主要非常不确定或无定论。总体而言，现有关于接受锥切术女性接种HPV疫苗的证据主要基于NRSI，存在严重或关键的偏倚风险，证据确定性为低到极低。RCT的证据有限（即仅有两项RCT）。额外的RCT对照组采用安慰剂干预，以评估HPV疫苗接种（特别是九价疫苗）作为锥切术辅助手段的疗效和安全性，将提供更有力的证据。未来的RCT还应旨在评估锥切术前后接种疫苗的效果如何因是否之前接受过HPV疫苗的一级预防、HPV疫苗接种与锥切术的时间关系以及不同年龄组而有所不同。
欧盟健康计划。
PROSPERO（CRD42023428998）。
